Tetraisoquinoline compounds which have useful pharmaceutical utility

ABSTRACT

Tetrahydroisoquinoline compounds of formula I ##STR1## and pharmaceutically acceptable salts and lipophilic ester thereof have utility as analgesics and in the treatment of psychoses, Parinson&#39;s disease, Lesch-Nyan syndrome, attention deficit disorder or cognitive impairment or in the relief of drug dependence or tardive dyskinesia.

This application is filed under 35 U.S.C. 371 as national stage entry ofPCT/EP92/02900, filed 12 Dec. 1992.

The present invention relates to novel tetrahydroisoquinoline compounds,to pharmaceutical compositions containing the compounds, methods ofpreparing the compounds and the use of the compounds in analgesia and inthe treatment of psychoses (for example schizophrenia), Parkinsons'sdisease, Lesch-Nyan syndrome, attention deficit disorder or cognitiveimpairment or in the relief of drug dependence or tardive dyskinesia.

The present invention provides tetrahydroisoquinoline compounds offormula I ##STR2## and pharmaceutically acceptable salts thereof, inwhich:

R₁ represents one or more substituents selected from H, halo, hydroxy,alkyl of 1 to 3 carbon atoms (optionally substituted by hydroxy), alkoxyof 1 to 3 carbon atoms, alkylthio of 1 to 3 carbon atoms, alkylsulphinylof 1 to 3 carbon atoms, alkylsulphonyl of 1 to 3 carbon atoms, nitro,cyano, polyhaloalkyl of 1 to 3 carbon atoms, polyhaloalkoxy of 1 to 3carbon atoms, phenyl (optionally substituted by one or more substituentsselected from halo, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3carbon atoms), or R₁ is carbamoyl optionally alkylated by one or twoalkyl groups each independently of 1 to 3 carbon atoms;

R₂ represents an aliphatic group containing 1 to 3 carbon atomsoptionally substituted by hydroxy or alkoxy containing 1 to 3 carbonatoms;

E represents an alkylene chain containing 2 to 5 carbon atoms optionallysubstituted by one or more alkyl groups containing 1 to 3 carbon atoms,

and G represents phenyl or phenyl substituted by one or moresubstituents which may be the same or different, and which areindependently alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbonatoms, halo, hydroxy, polyhaloalkyl of 1 to 3 carbon atoms,polyhaloalkoxy of 1 to 3 carbon atoms, cyano, alkylthio of 1 to 3 carbonatoms, alkylsulphinyl of 1 to 3 carbon atoms, alkylsulphonyl of 1 to 3carbon atoms, phenyl (optionally substituted by one or more substituentsselected from halo, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3carbon atoms), carbamoyl optionally alkylated by one or two alkyl groupseach independently of 1 to 3 carbon atoms, or G represents a phenyl ringhaving fused thereto a heterocyclic or aromatic carbocyclic ring;

and O-acylated derivatives thereof.

In preferred compounds of formula I, the hydroxy group is in the7-position. Accordingly one group of preferred compounds of theinvention is represented by formula II ##STR3## and pharmaceuticallyacceptable salts thereof, in which R₁, R₂, E and G are as defined aboveand O-acylated derivatives thereof.

A preferred group of O-acylated derivatives of compounds of formula I isrepresented by compounds of formula III ##STR4## and pharmaceuticallyacceptable salts thereof, in which R₁, R₂, E and G are as defined aboveand R₇ represents an acyl group derived from a carboxylic acid having 6to 20 carbon atoms preferably 7 to 18 carbon atoms. In more preferredcompounds of formula III, R₇ represents heptanoyl, decanoyl, dodecanoyl,hexadecanoyl or octadecanoyl. In most preferred compounds of formulaIII, the group OR₇ is in the 7-position.

In preferred compounds of formula I, II or III, R₁ represents H, halo,hydroxy, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms,alkylthio of 1 to 3 carbon atoms, nitro, polyfluoroalkyl of 1 to 3carbon atoms, polyfluoroalkoxy of 1 to 3 carbon atoms or phenyloptionally substituted by fluoro, chloro, bromo, methyl or methoxy. Inmore preferred compounds of formula I, II or III, R₁ represents H,fluoro, chloro, bromo, hydroxy, methyl, methoxy, phenyl or nitro. Inparticularly preferred compounds of formula II, R₁ represents onesubstituent in the 6-position which is H, fluoro, chloro, bromo,hydroxy, methyl, methoxy or phenyl.

In preferred compounds of formula I, II or III, R₂ represents an alkylgroup containing 1 to 3 carbon atoms (for example methyl or ethyl)optionally substituted by hydroxy (for example R₂ is 2-hydroxyethyl) orby methoxy (for example R₂ is 2-methoxyethyl) or R₂ represents analkenyl group of 2 or 3 carbon atoms (for example allyl).

In preferred compounds of formula I, II or III, the group E represents--(CH₂)₂ --, --(CH₂)₃ --, --(CH₂)₄ --, --(CH₂)₅ -- or --CH₂ CMe₂ CH₂ --.In particularly preferred compounds of formula I or II, E represents--(CH₂)₂ -- or --(CH₂)₃ --.

In preferred compounds of formula I, II or III, G represents phenyl orphenyl substituted by one or more substituents which are independentlyalkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halo,hydroxy, polyfluoroalkyl of 1 to 3 carbon atoms, polyfluoroalkoxy of 1to 3 carbon atoms or phenyl optionally substituted by fluoro, chloro,bromo, methyl or methoxy or G represents naphthyl ordihydrobenzofuran-7-yl.

In more preferred compounds of formula I, II or III, G represents phenylor phenyl optionally substituted by methyl, hydroxy, methoxy,methylthio, fluoro, chloro, bromo, trifluoromethyl, cyano ortrifluoromethoxy or G represents a naphthyl or dihydrobenzo[b]furan-7-ylgroup. In particularly preferred compounds of formula I, II or III, Grepresents phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl,3,4-dichlorophenyl, 4-fluorophenyl, 2-bromophenyl, 2-methylphenyl,2-methylthiophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,4-hydroxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethoxyphenyl,2-cyanophenyl, 2-bromo-4,5-dimethoxyphenyl, 1-naphthyl, 2-naphthyl or2,3-dihydrobenzo[b]furan-7-yl.

Specific compounds of formula I are:

6,7-dihydroxy-2-methyl-1-(1-phenylcyclopropyl)-1,2,3,4-tetrahydroisoquinoline.

6,7-dihydroxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline.

6,7-dihydroxy-2-methyl-1-(3,3-dimethyl-1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline.

6,7-dihydroxy-2-methyl-1-(1-phenylcyclopentyl)-1,2,3,4-tetrahydroisoquinoline.

6,7-dihydroxy-2-methyl-1-(1-phenylcyclohexyl)-1,2,3,4-tetrahydroisoquinoline.

1-[1-(4-chlorophenyl)cyclopropyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(4-chlorophenyl)cyclobutyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(4-chlorophenyl)cyclopentyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(4-chlorophenyl)cyclohexyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(4-chlorophenyl)cyclobutyl]-2-ethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline.

2-allyl-1-[1-(4-chlorophenyl)cyclobutyl]-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-chlorophenyl)cyclobutyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(3-chlorophenyl)cyclobutyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(3,4-dichlorophenyl)cyclobutyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2,4-dichlorophenyl)cyclobutyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(4-bromophenyl)cyclobutyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-bromophenyl)cyclobutyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(4-fluorophenyl)cyclobutyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-fluorophenyl)cyclobutyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

6,7-dihydroxy-2-methyl-1-[1-(2-methylthiophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline.

6,7-dihydroxy-2-methyl-1-[1-(2-trifluoromethylphenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline.

6,7-dihydroxy-2-methyl-1-[1-(3-trifluoromethylphenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline.

6,7-dihydroxy-2-methyl-1-[1-(o-tolyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline.

6,7-dihydroxy-2-methyl-1-[1-(4-biphenylyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline.

6,7-dihydroxy-1-[1-(4-methoxyphenyl)cyclobutyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline.

6,7-dihydroxy-1-[1-(4-hydroxyphenyl)cyclopentyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-cyanophenyl)cyclobutyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

6,7-dihydroxy-2-methyl-1-[1-(2-naphthyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline.

7-hydroxy-6-methoxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline.

7-hydroxy-6-methoxy-2-methyl-1-(1-phenylcyclopentyl)-1,2,3,4-tetrahydroisoquinoline.

7-hydroxy-6-methoxy-2-methyl-1-(1-phenylcyclohexyl)-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-bromophenyl)cyclobutyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(4-chlorophenyl)cyclobutyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-chlorophenyl)cyclobutyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-chlorophenyl)-3,3-dimethylcyclobutyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-chlorophenyl)cyclopentyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline

1-[1-(2,4-dichlorophenyl)cyclobutyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

7-hydroxy-6-methoxy-1-[1-(2-methoxyphenyl)cyclopropyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinoline.

7-hydroxy-6-methoxy-1-[1-(2-methoxyphenyl)cyclobutyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline.

7-hydroxy-6-methoxy-1-[1-(3-methoxyphenyl)cyclobutyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline.

7-hydroxy-6-methoxy-2-methyl-1-[1-(4-trifluoromethoxyphenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2,3-dihydrobenzo[b]furan-7-yl)cyclopropyl]-7-hydroxy -6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

7-hydroxy-6-methoxy-2-methyl-1-[1-(1-naphthyl)cyclopropyl]-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-bromo-4,5-dimethoxyphenyl)cyclobutyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-chlorophenyl)cyclobutyl]-7-hydroxy-2-methyl-6-phenyl-1,2,3,4-tetrahydroisoquinoline.

6-fluoro-7-hydroxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline.

1-[1-(4-chlorophenyl)cyclobutyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-chlorophenyl)cyclobutyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2,4-dichlorophenyl)cyclobutyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2,4-dichlorophenyl)cyclopropyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(4-bromophenyl)cyclobutyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-bromophenyl)cyclobutyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

6-chloro-7-hydroxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline.

2-allyl-6-chloro-7-hydroxy-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline.

6-chloro-7-hydroxy-2-methyl-1-(3,3-dimethyl-1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline.

6-chloro-1-[1-(4-chlorophenyl)cyclobutyl]-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

6-chloro-1-[1-(2-chlorophenyl)cyclobutyl]-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-bromophenyl)cyclobutyl]-6-chloro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

7-chloro-6-hydroxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline.

5-chloro-8-hydroxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline.

5-chloro-6,7-dihydroxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline.

6,8-dichloro-7-hydroxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline.

7-hydroxy-2-methyl-6-nitro-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline.

6-bromo-7-hydroxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydrosoqunoline.

1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

7-hydroxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline.

1-[1-(4-chlorophenyl)cyclobutyl]-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-chlorophenyl)cyclobutyl]-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-2,6-dimethyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(2-chlorophenyl)cyclobutyl]-7-hydroxy-2,6-dimethyl-1,2,3,4-tetrahydroisoquinoline.

1-[1-(4-chlorophenyl)cyclobutyl]-5-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

and pharmaceutically acceptable salts thereof in the form of individualenantiomers, racemates or other mixtures of enantiomers.

Compounds of formula I, II and III may exist as salts withpharmaceutically acceptable acids. Examples of such salts includehydrochlorides, hydrobromides, hydriodides, sulphates, nitrates,maleares, acetates, citrates, fumarates, tartrates, succinates,benzoates, pamoates, methylsulphates, dodecanoates and salts with acidicamino acids such as glutamic acid. Compounds of formula I, II and IIIand their salts may exist in the form of solyates (for examplehydrates).

Compounds of formula III have high lipid solubility, and are thereforesuitable for use in the so-called depot formulations which provide asource of active compound which is located within the body (eg byintramuscular injection). These compounds may be formulated in apharmaceutically acceptable oil.

Specific compounds of formula III are:

1-[1-(2-chlorophenyl)cyclopropyl]-7-heptanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline

1-[1-(2-chlorophenyl)cyclopropyl]-7-decanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline

1-[1-(2-chlorophenyl)cyclopropyl]-7-dodecanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline

1-[1-(2-chlorophenyl)cyclopropyl]-7-hexadecanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline

1-[1-(2-chlorophenyl)cyclopropyl]-7-octadecanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline

1-[1-(2-chlorophenyl)cyclopropyl]-7-decanoyloxy-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline

1-[1-(2-chlorophenyl)cyclobutyl]-7-decanoyloxy-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline

and pharmaceutically acceptable salts thereof in the form of individualenantiomers, racemates or other mixtures of enantiomers.

It will be appreciated by those skilled in the art that compounds offormula I, II and III contain a chiral centre. When a compound offormula I, II and III contains a single chiral centre it exists in twoenantiomeric forms. The present invention includes the individualenantiomers and mixtures of those enantiomers. The enantiomers may beobtained by methods known to those skilled in the art. Such methodstypically include resolution via formation of diastereoisomeric saltswhich may be separated, for example, by crystallisation; via formationof diastereoisomeric derivatives or complexes which may be separated,for example, by crystallisation, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic esterification, oxidation or reduction;or gas-liquid or liquid chromatography in a chiral environment, forexample on a chiral support such as silica with a bound chiral ligand orin the presence of a chiral solvent. It will be appreciated that wherethe desired enantiomer is converted into another chemical entity by oneof the separation processes described above, a further step willsubsequently be required to liberate the desired enantiomeric form.Alternatively, specific enantiomers may be synthesised by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting one enantiomer into the other by asymmetrictransformation.

Specific enantiomeric forms of compounds of formula I are:

(-)-6-chloro-7-hydroxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline

(+)-1-[1-(2-bromophenyl)cyclobutyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide

(+)-1-[1-(2-chlorophenyl)cyclobutyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide

(+)-1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide

(+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide

(+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-2,6-dimethyl-1,2,3,4-tetrahydroisoquinolinehydrobromide

(+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-heptanoyloxy-1,2,3,4-tetrahydroisoquinoline

(+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-decanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline

(+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-dodecanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline

(+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-hexadecanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline

(+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-octadecanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline

(-)-1-[1-(2-chlorophenyl)cyclobutyl]-7-decanoyloxy-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline

(+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-decanoyloxy-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline.

When a compound of formula I, II or III contains more than one chiralcentre it may exist in diastereoisomeric forms. The diastereoisomericpairs may be separated by methods known to those skilled in the art, forexample chromatography or crystallisation and the individual enantiomerswithin each pair may be separated as described above. The presentinvention includes each diastereoisomer of compounds of formula I or IIand mixtures thereof.

Certain compounds of formula I, II or III may exist in more than onecrystal form and the present invention includes each crystal form andmixtures thereof.

The present invention also provides pharmaceutical compositionscomprising a therapeutically effective amount of a compound of formulaI, II or III together with a pharmaceutically acceptable diluent orcarrier. Such pharmaceutical formulations may be used in analgesia andin the treatment of psychoses (for example schizophrenia), Parkinson'sdisease, Lesch-Nyan syndrome, attention deficit disorder or cognitiveimpairment or in the relief of drug dependence or tardive dyskinesia.

In therapeutic use, the active compound may be administered orally,rectally, parenterally or topically, preferably orally. Thus thetherapeutic compositions of the present invention may take the form ofany of the known pharmaceutical compositions for oral, rectal,parenteral or topical administration. Pharmaceutically acceptablecarriers suitable for use in such compositions are well known in the artof pharmacy. The compositions of the invention may contain 0.1-90% byweight of active compound. The compositions of the invention aregenerally prepared in unit dosage form.

Compositions for oral administration are the preferred compositions ofthe invention and these are the known pharmaceutical forms for suchadministration, for example tablets, capsules, granules, syrups,solutions and aqueous or oil suspensions. The excipients used in thepreparation of these compositions are the excipients known in thepharmacist's art. Tablets may be prepared from a mixture of the activecompound with fillers, for example calcium phosphate; disintegratingagents, for example maize starch; lubricating agents, for examplemagnesium stearate; binders, for example micro-crystalline cellulose orpolyvinylpyrrolidone and other optional ingredients known in the art topermit tableting the mixture by known methods. The tablets may, ifdesired, be coated using known methods and excipients which may includeenteric coating using for example hydroxypropylmethylcellulosephthalate. The tablets may be formulated in a manner known to thoseskilled in the art so as to give a sustained release of the compounds ofthe present invention. Such tablets may, if desired, be provided withenteric coatings by known methods, for example by the use of celluloseacetate phthalate. Similarly, capsules, for example hard or soft gelatincapsules, containing the active compound with or without addedexcipients, may be prepared by known methods and, if desired, providedwith enteric coatings in a known manner. The contents of the capsule maybe formulated using known methods so as to give sustained release of theactive compound. The tablets and capsules may conveniently each contain1 to 500 mg of the active compound.

Other compositions for oral administration include, for example, aqueoussuspensions containing the active compound in an aqueous medium in thepresence of a non-toxic suspending agent such as sodiumcarboxymethylcellulose, and oily suspensions containing a compound ofthe present invention in a suitable vegetable oil, for example arachisoil. The active compound may be formulated into granules with or withoutadditional excipients. The granules may be ingested directly by thepatient or they may be added to a suitable liquid carrier (for example,water) before ingestion. The granules may contain disintegrants, eg aneffervescent couple formed from an acid and a carbonate or bicarbonatesalt to facilitate dispersion in the liquid medium.

Compositions of the invention suitable for rectal administration are theknown pharmaceutical forms for such administration, for example,suppositories with hard fat or polyethylene glycol bases.

Compositions of the invention suitable for parenteral administration arethe known pharmaceutical forms for such administration, for examplesterile suspensions or sterile solutions in a suitable solvent.

Compositions for topical administration may comprise a matrix in whichthe pharmacologically active compounds of the present invention aredispersed so that the compounds are held in contact with the skin inorder to administer the compounds transdermally. Alternatively theactive compounds may be dispersed in a pharmaceutically acceptablecream, gel or ointment base. The amount of active compound contained ina topical formulation should be such that a therapeutically effectiveamount of the compound is delivered during the period of time for whichthe topical formulation is intended to be on the skin.

The compounds of the present invention may also be administered bycontinuous infusion either from an external source, for example byintravenous infusion or from a source of the compound placed within thebody. Internal sources include implanted reservoirs containing thecompound to be infused which is continuously released for example byosmosis and implants which may be (a) liquid such as a suspension orsolution in a pharmaceutically acceptable oil of the compound to beinfused for example in the form of a very sparingly water-solublederivative such as a dodecanoate salt or a compound of formula III asdescribed above or (b) solid in the form of an implanted support, forexample of a synthetic resin or waxy material, for the compound to beinfused. The support may be a single body containing all the compound ora series of several bodies each containing part of the compound to bedelivered. The amount of active compound present in an internal sourceshould be such that a therapeutically effective amount of the compoundis delivered over a long period of time.

In some formulations it may be beneficial to use the compounds of thepresent invention in the form of particles of very small size, forexample as obtained by fluid energy milling.

In the compositions of the present invention the active compound may, ifdesired, be associated with other compatible pharmacologically activeingredients.

The pharmaceutical compositions containing a therapeutically effectiveamount of a compound of formula I, II or III may be used in analgesia orto treat psychoses (for example schizophrenia), Parkinson's disease,Lesch-Nyan syndrome, attention deficit disorder or cognitive impairmentor in the relief of drug dependence or tardive dyskinesia. In suchtreatment the amount of the compound of formula I or II which will beadministered orally, rectally or parenterally per day is in the range0.1 to 5000 mg preferably 5 to 500 mg given in a single or in divideddoses at one or more times during the day.

Processes for the preparation of compounds of formula I will now bedescribed. These processes form a further aspect of the presentinvention.

Compounds of formula I may be prepared by the cleavage of compounds offormula IV ##STR5## in which R₃ is an optionally substituted alkyl group(e.g. methyl or benzyl) and R₄ is the group R₁ or a group which can beconverted into the group R₁. Demethylation may be effected by thereaction with hydrobromic acid optionally in the presence of glacialacetic acid, with boron tribromide, with pyridine hydrochloride, withsodium methanethiolate or with trimethyliodosilane. Debenzylation may beeffected by hydrolysis e.g. acid hydrolysis or by hydrogenolysis, forexample using a palladium/charcoal catalyst. Compounds of formula I inwhich R₁ is hydroxy may be prepared by cleavage of compounds of formulaIV in which the groups OR₃ and R₄ are the same (e.g. methoxy orbenzyloxy). The cleavage of the group R₄ will occur simultaneously withthe cleavage of the group OR₃.

Compounds of formula I may be prepared by the alkylation or alkenylationof compounds of formula V ##STR6## under conditions which do not resultin alkylation or alkenylation of the hydroxy group. For example,compounds of formula I in which R₂ is methyl may be prepared by themethylation of compounds of formula V, for example, using formaldehydeand formic acid or formaldehyde and sodium cyanoborohydride.

Compounds of formula I in which R₁ is other than H may be prepared bysubstitution reactions which will be well known to those skilled in theart. For example, compounds of formula I in which R₁ is nitro may beprepared by the nitration of compounds of formula I in which R₁ is Husing nitric acid and compounds of formula I in which R₁ represents oneor more chloro atoms may be prepared from compounds of formula I inwhich R₁ is H by chlorination using, for example sodium hypochlorite andhydrochloric acid.

Compounds of formula II may be prepared by methods analogous to thosedescribed above for the preparation of compounds of formula I.

Compounds of formula III may be prepared from compounds of formula I byreaction with an acylating agent for example a carboxylic acid chlorideof formula R₇ Cl or a carboxylic anhydride of formula (R₇)₂ O.

Compounds of formula IV may be prepared by the alkylation oralkenylation of compounds of formula VI ##STR7## for example by reactionwith an alkyl halide (e.g. methyl iodide) or an alkenyl halide (e.g.allyl iodide or bromide). Compounds of formula IV may be prepared byreductive alkylation of compounds of formula VI, for example, byreaction with an aldehyde or ketone and a reducing agent. For example,compounds of formula IV in which R₂ is methyl may be prepared by themethylation of compounds of formula VI, for example, using formaldehydeand formic acid, formaldehyde and sodium dihydrogen phosphite orformaldehyde and sodium cyanoborohydride.

Compounds of formula IV in which R₂ is methyl may be prepared by thereaction of compounds of formula VII ##STR8## in which R₅ is the groupR₃ under conditions which result in the reduction and methylation of thecompound of formula VII, for example by the reaction of the compound offormula VII with formaldehyde and a reducing agent such as sodiumcyanoborohydride.

Compounds of formula IV may be prepared by the reaction of compounds offormula VIII ##STR9## in which R₆ is the group R₂ with a compound offormula IX ##STR10## in the presence of an acid, for examplehydrochloric acid.

Compounds of formula IV may be prepared by the reduction of compounds offormula X ##STR11## in which Q.sup.⊖ is a suitable anion such as iodideor methylsulphate with, for example, sodium borohydride, sodiumcyanoborohydride, borane, borane-dimethylsulphide complex, lithiumaluminium hydride or by catalytic hydrogenation. Chiral reducing agentssuch as chiral sodium triacyloxyborohydrides {for example theappropriate enantiomers of tris(N-benzyloxycarbonylprolyloxy)borohydrideor tris[N-(2-methylpropyloxycarbonyl)prolyloxy]borohydride}, chiraldialkyloxyboranes, chiral oxazaborolidines may be used to give one ofthe enantiomers of the compound of formula IV. One of the enantiomers ofcompounds of formula IV may be prepared by catalytic hydrogenation usinga chiral catalyst. A suitable catalyst is the complex formed by thereaction of a chiral phosphine [for example,2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane]witha transition metal complex [for example,chloro(1,5-cyclooctadiene)rhodium (I) dimer].

Compounds of formula V may be prepared by the cleavage of compounds offormula VI in which R₄ is the group R₁ or a group which can be convertedinto the group R₁ in a similar manner to that described above in respectof compounds of formula I.

Compounds of formula V may be prepared by the reduction of compounds offormula VII in which R₅ is H, for example using reduction reactionssimilar to those described above for the reduction of compounds offormula X. Chiral reducing agents may be used to give one of theenantiomers of the compound of formula V in a similar manner to thatdescribed above for the reduction of compounds of formula X.

Compounds of formula VI may be prepared by the reduction of compounds offormula VII in which R₅ is the group R₃ in a similar manner to thatdescribed above for the preparation of compounds of formula IV and V.

Compounds of formula VI may be prepared by reduction of compounds offormula XI ##STR12## for example using catalytic hydrogenation.

Compounds of formula VI may be prepared by the reaction of a compound offormula VIII in which R₆ is H with a compound of formula IX in thepresence of an acid for example hydrochloric acid.

Compounds of formula VII may be prepared by the cyclisation of compoundsof formula XII ##STR13## in which R₅ is H or R₃. The cyclisation may beeffected in the presence of a condensing agent such as phosphorusoxychloride, phosphorus pentoxide, phosphorus pentachloride,polyphosphoric ester, polyphosphoric acid, zinc chloride, hydrochloricacid, thionyl chloride or sulphuric acid.

Compounds of formula VII may be prepared by the reaction of a compoundof formula XIII ##STR14## with a halo-substituted group of formula X-Gin which X is halo (for example fluoro) in the presence of a base suchas lithium diisopropylamide.

Compounds of formula IX may be prepared by reduction ofarylcycloalkanecarbonitriles of formula XIV ##STR15## bydi-t-butylaluminium hydride or di-isobutyl aluminium hydride orreduction of arylcycloalkane carbonyl chlorides of formula XV ##STR16##with tri-t-butoxy aluminohydride.

Compounds of formula X may be prepared by the reaction of a compound offormula VII in which R₅ is the group R₃ with an alkylating agent offormula R₂ Q, for example methyl iodide or dimethylsulphate.

Compounds of formula XI may be prepared by the cyclisation of compoundsof formula XVI ##STR17##

The cyclisation may be effected in the presence of an acid such assulphuric acid.

Compounds of formula XII may be prepared by the reaction of aphenethylamine of formula XVII ##STR18## in which R₅ is H or R₃ with anarylcycloalkanecarbonyl chloride of formula XV for example in thepresence of an organic base such as triethylamine. Compounds of formulaXII may be prepared by the condensation of a phenethylamine of formulaXVII with an arylcycloalkane carboxylic acid of formula XVIII ##STR19##or an ester thereof, for example by fusion or by the action of acondensing agent such as carbonyldiimidazole.

Compounds of formula XIII may be prepared by cyclisation of compounds offormula XIX ##STR20## under conditions similar to those described abovefor the cyclisation of compounds of formula XII.

Arylcycloalkanecarbonitriles of formula XIV may be prepared by thereaction of an arylacetonitrile of formula XX

    G--CH.sub.2 --CN                                           XX

with a dihalo compound of formula XXI

    Z--E--Z'                                                   XXI

in which Z and Z', which may be the same or different, are leavinggroups such as halo e.g. chloro or bromo in the presence of a base suchas sodium hydride or potassium hydroxide.

Arylcycloalkanecarbonyl chlorides of formula XV may be prepared fromarylcycloalkane carboxylic acids of formula XVIII by methods which arewell known in the art, for example, by reaction with thionyl chloride.

Compounds of formula XVI may be prepared by the reaction of a compoundof formula XXII ##STR21## with a haloacetaldehyde dimethylacetal forexample chloroacetaldehyde dimethylacetal.

Arylcycloalkane carboxylic acids of formula XVIII may be prepared by thehydrolysis (e.g. basic hydrolysis) of arylcycloalkanecarbonitriles offormula XIV or by the reaction of hydrogen peroxide witharylcycloalkanecarbonitriles of formula XIV in the presence of a basefollowed by reaction with nitrous acid to give the required carboxylicacid.

Compounds of formula XIX may be prepared by the reaction of aphenylethylamine of formula XVII with a cycloalkane carbonyl chloride offormula XXIII ##STR22##

Compounds of formula XXII may be prepared by the reaction of a compoundof formula XXIV ##STR23## in which Y is halo (eg chloro or bromo) withan arylcycloalkanecarbonitrile of formula XIV followed by reductionwith, for example, sodium borohydride.

Compounds of formula XXIV may be prepared by the reaction of magnesiumwith a compound of formula XXV ##STR24## in which Y is halo (eg bromo orchloro).

The ability of compounds of formula I or formula II to interact withdopamine receptors has been demonstrated by the following tests whichdetermine the ability of the compounds to inhibit tritiated ligandbinding to dopamine receptors in vitro and in particular to the D1 andD2 dopamine receptors.

Striatal samples from the brains of male Charles River CD rats weighingbetween 140-250 g were homogenised in ice-cold 50 mM Tris-HCl buffer (pH7.4 when measured at 25° C. for D1 binding assays and pH 7.7 whenmeasured at 25° C. for D2 binding assays) and centrifuged for 10 minutes(at 21,000 g when used for D1binding assay and 40,000 g when used forD2binding assays). The pellet was resuspended in the same buffer, againcentrifuged and the final pellet stored at -80° C. Before each test thepellet was resuspended in 50 mM Tris-HCl buffer containing 120 mM NaCl,5 mM KCl, 2 mM CaCl₂ and 1 mM MgCl₂ at pH 7.4 for the D1 binding assaysand at pH 7.7 with the addition of 6 mM ascorbic acid for the D2 bindingassays. Aliquots of this suspension were then added to tubes containingthe ligand and either the compound under test or buffer. For the D1binding assays the ligand was tritiated SCH 23390 and the mixture wasincubated at 37° C. for 30 minutes before the incubation was terminatedby rapid filtration. For the D2 binding assays the ligand was tritiated(S)-sulpiride and the mixture was incubated at 4° C. for 40 minutesbefore the incubation was terminated by rapid filtration. Non-specificbinding was determined experimentally by the addition of saturatingconcentrations of chloropromazine or spiroperidol for D1 and D2receptors respectively.

The filters were washed with ice-cold Tris-HCl buffer and dried. Thefilters were punched out on to vials containing scintillation fluid andwere left for about 20 hours before being counted by scintillationspectrophotometry. Displacement curves were produced over a range ofconcentrations of the compound under test and the concentration whichgave a 50% inhibition of specific binding (IC50) obtained from thecurve. The inhibition coefficient Ki was then calculated using theformula ##EQU1## in which [ligand] is the concentration of the tritiatedligand used and K_(D) is the equilibrium dissociation constant for theligand.

The K_(i) values obtained in the above tests for D1 and D2 binding foreach of the final products of Examples 1 to 85 hereinafter are given inTable I below which also shows the ratio between these two values to twosignificant figures. In some cases K_(i) values for D2 binding wereestimated from single concentration data by the application of theLangmuir adsorption isotherm equation. These cases are indicated by an"E" in the last two columns of Table I. In other cases it was notpossible to determine or estimate the K_(i) and the K_(i) value is givenas greater than (>) that which would result from the application of theabove formula to the highest concentration which displaced ≦50% of theligand.

                  TABLE I                                                         ______________________________________                                                 K.sub.i for D1                                                                             K.sub.i for D2                                                                           K.sub.i for D2                               Example  binding (nM) binding (nM)                                                                             K.sub.i for D1                               ______________________________________                                        1        4.0          1000       250                                          2        7.2          12000      1700                                         3        22           6100000    280000                                       4        29           260000     9000                                         5        8.3          32000      3900                                         6        3            41000      14000                                        7        21           2900       140                                          8        310          >5000      >16                                          9        1.9          1800       950                                          10       1.6          2500       1600                                         11       150.0        3500       23                                           12       1.4          710        510                                          13       44           3700       84                                           14       120          4800       40                                           15       200          >5000      >25                                          16       180          3200       18                                           17       3.9          8900       2300                                         18       83           4400       53                                           19       190          7000E      37E                                          20       31           >5000      >160                                         21       200          >5000      >25                                          22       2.3          1800       780                                          23       18           15000      830                                          24       1.9          1700       890                                          25       19           5400000    280000                                       26       560          7000E      13E                                          27       190          5700       30                                           28       11           3600       330                                          29       120          7000E      58E                                          30       66           >5000      >76                                          31       540          11000E     20E                                          32       140          >5000      >36                                          33       65           23000      350                                          34       1.8          7800       4300                                         35       1.3          240000     180000                                       36       62           4400       71                                           37       0.6          5300       8800                                         38       4.1          3400       830                                          39       23           1900       83                                           40       0.4          18000      45000                                        41       79           13000      160                                          42       170          2500       15                                           43       1.4          860        610                                          44       130          4800       37                                           45       24           >500       >21                                          46       6.6          1200       180                                          47       9.1          19000      2100                                         48       94           3000E      32E                                          49       8.4          >500       >60                                          50       25           1500       60                                           51       13           >500       >38                                          52       17           5400       320                                          53       24           7600       320                                          54       32           3000       94                                           55       41           >500       >12                                          56       2.3          52000      23000                                        57       770          >5000      >6.5                                         58       740          360000     490                                          59       5.2          3200       620                                          60       2.8          2000       710                                          61       0.18         450        2500                                         62       0.38         410        1100                                         63       2.0          1600       800                                          64       2.4          4800       2000                                         65       22           51000      2300                                         66       120          >500       >4.2                                         67       53           7000E      130E                                         68       2            1900       950                                          69       2.1          5800       2800                                         70       21           35000      1700                                         71       1.5          1800       1200                                         72       47           9500       200                                          73       0.9          5000       5500                                         74       1.5          1100       730                                          75       150.0        >5000      >33                                          76       60.0         >5000      >83                                          77       0.28         900        3200                                         78       94           550        5.9                                          79       1.2          940        780                                          80       0.67         370        550                                          81       1.9          330        170                                          82       1.8          4900       2700                                         83       21           6600E      310E                                         84       12           5100       430                                          85       0.28         900        3200                                         ______________________________________                                    

The invention is illustrated by the following Examples which are givenby way of example only. In these Examples all temperatures are given indegrees Celsius. The final products of each of these Examples werecharacterised by one or more of the following procedures: elementalanalyses, nuclear magnetic resonance spectroscopy and infra redspectroscopy.

EXAMPLES 1 to 11 ##STR25##

A compound of formula IV (a g, prepared as described in the Exampleidentified in column SM) in which R₂ is methyl, OR₃ and R₄ are asdefined in Table A and E is --(CH₂)₃ -- was heated under reflux with 48%aqueous hydrobromic acid (b ml) and glacial acetic acid (c ml) for dhours to give a compound of formula II in which R₁ is as defined inTable A, R₂ is methyl and E is --(CH₂)₃ --. The solvent was removed byevaporation and the residue dried by repeated azeotropic distillationwith propan-2-ol. The product was isolated as its hydrobromide salt (themelting point in degrees Celsius is given in the column headed "mp").The isolation procedure and any other variations from the aboveprocedure are identified in the column headed "Note".

NOTES TO TABLE A

A1 The product was precipitated from its concentrated solution inpropan-2-ol.

A2 The residue from the azeotropic distillation was dried in vacuo at100° C. for 21/2 hours, then decolourised with charcoal in propan-2-ol,washed with ether, propan-2-ol (1-2ml) and ether and dried in vacuo.

A3 The residue from the azeotropic distillation was recrystallised frompropan-2-ol to give the desired product.

A4 The residue from the azeotropic distillation gave the desired productwhich was used without further purification.

A5 The reaction was conducted under nitrogen. The residue from theazeotropic distillation was partitioned between ether and saturatedaqueous sodium bicarbonate solution. The ether layer was dried andtreated with oxalic acid. The resulting oxalate salt was collected byfiltration, washed with ether and dried at 50° C. in vacuo. The meltingpoint of the oxalate salt is given in the last column of Table A.

A6 The reaction was conducted under nitrogen. The residue after theazeotropic distillation was decolourised with charcoal in methanol andthe resulting material dried by azeotropic distillation withpropan-2-ol. The resulting residue was decolourised with charcoal inethanol. The solution yielded the product on evaporation.

A7 The residue after azeotropic distillation was decolourised withcharcoal in methanol. The residue was partitioned between ether andsaturated aqueous sodium bicarbonate solution. The ether layer wastreated with an ethereal solution of oxalic acid. The resulting solidwas washed with ether and dried in vacuo. The melting point of theoxalate salt is given in the last column of Table A.

A8 The reaction was conducted under nitrogen. The residue resulting fromthe removal of the solvent from the reaction mixture was dissolved inindustrial methylated spirit and decolourised with charcoal. The solventwas removed and the residue washed with ether, dissolved in ethanol, anddecolourised with charcoal. Concentration of the solution yielded thedesired product which was washed with ether.

A9 The reaction was conducted under nitrogen. The solvent was removedfrom the reaction mixture by distillation and the residue dissolved inmethanol and decolourised with charcoal. Filtration and evaporation gavea residue which was dried by azeotropic distillation with propan-2-ol.The product was crystallised from propan-2-ol, collected by filtration,washed with ether and dried in vacuo at 80° C.

A10 The residue from the azeotropic distillation was partitioned betweenether and saturated aqueous sodium bicarbonate solution. The ether layeryielded a residue which was heated under reflux with 48% aqueoushydrobromic acid (15 ml) and glacial acetic acid (15 ml) for 5 hours.The reaction mixture was neutralised with saturated aqueous sodiumbicarbonate solution and extracted with ether. The ether extract waswashed with 1M hydrochloric acid. The washings yielded a solid which wasdried in vacuo at 70° C., basified and extracted with ether. The extractgave a residue which was dissolved in ethanol and treated with etherealoxalic acid to Give the desired product in the form of its oxalate salt,the melting point of which is given in the last column of Table A.

A11 The reaction was conducted under nitrogen. The residue after theazeotropic distillation was decolourised with charcoal in methanol andthe resulting material triturated with propan-2-ol. The solid wascrystallised from ether, collected by filtration, washed with ether anddried in vacuo at 50° C.

                                      TABLE A                                     __________________________________________________________________________    Ex                                                                              R.sub.1                                                                           G       SM OR.sub.3                                                                          R.sub.4                                                                           a b c d  Note                                                                             mp (°C.)                          __________________________________________________________________________    1 6-OH                                                                              2-bromophenyl                                                                         MF1                                                                              7-OMe                                                                             6-OMe                                                                             2.1                                                                             20                                                                              20                                                                              16 A1 199-202                                  2 6-OH                                                                              2-chlorophenyl                                                                        MF2                                                                              7-OMe                                                                             6-OMe                                                                             4.6                                                                             25                                                                              25                                                                              16 A2 192                                      3 6-OH                                                                              4-fluorophenyl                                                                        MF3                                                                              7-OMe                                                                             6-OMe                                                                             5.9                                                                             30                                                                              30                                                                              16 A3 134                                                                           (dec)                                    4 6-OH                                                                              2-methylphenyl                                                                        MF4                                                                              7-OMe                                                                             6-OMe                                                                             4.5                                                                             25                                                                              25                                                                              16 A4 145                                                                           (dec)                                    5 6-F 4-chlorophenyl                                                                        MI1                                                                              7-OMe                                                                             6-F 3.5                                                                             20                                                                              20                                                                              8  A5 197-200                                                                       (dec)                                    6 6-F 4-bromophenyl                                                                         MI2                                                                              7-OMe                                                                             6-F 2.7                                                                             20                                                                              20                                                                              4  A6 140-145                                  7 6-OH                                                                              2-fluorophenyl                                                                        MF5                                                                              7-OMe                                                                             6-OMe                                                                             1.4                                                                             25                                                                              25                                                                              4  A7 155-158                                                                       (dec)                                    8 6-OH                                                                              3-trifluoro-                                                                          MI3                                                                              7-OMe                                                                             6-OMe                                                                             8.8                                                                             30                                                                              20                                                                              2.5                                                                              A8 148-150                                        methylphenyl                                                            9 6-F 2,4-dichloro-                                                                         MI4                                                                              7-OMe                                                                             6-F 2.7                                                                             20                                                                              20                                                                              4  A9 237-240                                        phenyl                                                                  10                                                                              6-Me                                                                              2-chlorophenyl                                                                        MF6                                                                              7-OMe                                                                             6-Me                                                                              3.3                                                                             13                                                                              13                                                                              5.5                                                                               A10                                                                             203-205                                                                       (dec)                                    11                                                                              6-Ph                                                                              2-chlorophenyl                                                                        MI6                                                                              7-OMe                                                                             6-Ph                                                                              4.3                                                                             20                                                                              20                                                                              18  A11                                                                             229-236                                  __________________________________________________________________________

EXAMPLE 12

1-[1-(2-Chlorophenyl)cyclopropyl]-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(0.25 g, prepared as described in Example MF7) was heated on a steambath at 100° C. in a solution of 48% hydrobromic acid (60 ml) andglacial acetic acid (60 ml) for 16 hours. The mixture was heated underreflux for 2 hours until the reaction was complete. The solvent wasremoved in vacuo and the residue dried by azeotropic distillation withpropan-2-ol. The resulting suspension was removed by filtration andcrystallised twice from ethanol to give1-(1-(2-chlorophenyl)cyclopropyl)-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide, which was characterised by elemental analysis.

EXAMPLES 13to 34 ##STR26##

A mixture of a compound of formula VI in which OR₃, R₄, E and G are asdefined in Table AA Part I (a g) anhydrous potassium carbonate (b g),methyl iodide (c g) and acetone (d ml) was stirred at ambienttemperature for e hours. The reaction mixture was filtered and treatedas set out in the Notes to Table AA part I to give a compound of formulaIV in which R₂ is methyl, OR₃, R₄, E and G are as defined in Table AAPart I which was used without being characterised in the next stage ofthe reaction.

A mixture of a compound of formula IV prepared by the procedure in theabove paragraph (f g), 48% hydrobromic acid (g ml) and glacial aceticacid (h ml) was heated under nitrogen under reflux for j hours to give acompound of formula I in which R₁ is as defined in Table AA Part II, R₂is methyl, the position of the hydroxy substituent is indicated in thecolumn headed POS in Table AA Part II and E and G are as defined inTable AA Part I. The desired product was isolated as described in theNotes to Table AA part II below.

NOTES TO TABLE AA

In column E of Table AA, W represents --CH₂.CMe₂.CH₂ --

AA1 A further portion of methyl iodide (0.1 g) was added after 3 hours.The reaction mixture was filtered and the solvent removed by evaporationto give a residue which was dissolved in dichloromethane. The solutionwas filtered and the solvent removed by evaporation to give a solidresidue which was used in the next stage.

AA2 The solvent was removed from the reaction mixture and the residuewas dried by azeotropic distillation with propan-2-ol. The residue wasthen decolourised with charcoal in propan-2-ol to give the hydrobromidesalt of the desired compound of formula I which was washed withpropan-2-ol and then ether and dried in vacuo. The melting point of thesalt is given in the last column of Table AA.

AA3 The desired product was obtained by filtering and removing thesolvent from the reaction mixture.

AA4 The solvent was removed from the reaction mixture. The solution wasdecolourised with charcoal in methanol, filtered and the solvent removedto give a residue which was crystallised from propan-2-ol to give thehydrobromide salt, the melting point of which is given in the lastcolumn of Table AA.

AA5 The solvent was removed from the reaction mixture and the residuewas partitioned between ether and water. The ether layer yielded thedesired product.

AA6 The residue from the concentrated reaction mixture was partitionedbetween ether and saturated aqueous sodium bicarbonate solution. Theether layer yielded a residue which was treated with ethereal HCl togive the hydrochloride salt which was recrystallised from propan-2-ol.The melting point of this salt is given in Table AA.

AA7 The hydrobromide salt precipitated from the reaction mixture. Themelting point of this salt is given in Table AA.

AA8 The residue from the reaction mixture was decolourised with charcoalin methanol, dried by azeotropic distillation with propan-2-ol andtriturated with propan-2-ol and ether to give the hydrobromide salt. Themelting point of the salt is given in Table AA.

AA9 The residue from evaporating the reaction mixture was decolourisedwith charcoal in propan-2-ol. The solvent was removed and the residuewashed with ether and decolourised with charcoal in acetone. The solventwas removed to give the hydrobromide salt, the melting point of whichcould not be determined as the product decomposed at around 150° C.

AA10 The starting material was a compound of formula VI in which G was4-methoxyphenyl. The methoxy group was converted into the desiredhydroxy group during the second stage of the reaction. The residue fromthe reaction mixture was partitioned between water and dichloromethane.The organic layer yielded the desired product.

AA11 The residue from the concentrated reaction mixture was partitionedbetween ether and saturated aqueous sodium bicarbonate solution. Theether layer yielded a residue which was treated with ethereal HCl togive the hydrochloride salt which was recrystallised from a 10:1 mixtureof ethanol and light petroleum ether (b.p. 60°-80° C.). The meltingpoint of this

salt is given in Table AA.

AA12 The residue from the evaporation of the solvent from the reactionmixture was decolourised with charcoal in propan-2-ol. The residue waswashed with petroleum ether (b.p. 60°-80°) and partitioned between ethylacetate and saturated aqueous sodium bicarbonate solution. The organiclayer yielded an oil which was treated with ether to give a precipitatewhich was separated by filtration. The filtrate was treated withethereal oxalic acid to give the oxalate salt of the desired productwhich was recrystallised from methanol. The melting point of this saltis given in Table AA.

AA13 The residue from evaporation of the solvent from the reactionmixture was treated with water, and extracted with ethyl acetate. Theorganic layer yielded the desired product which was used without furtherpurification.

AA14 The residue from the evaporation of the solvent from the reactionmixture was decolourised with charcoal in methanol, dried by azeotropicdistillation with propan-2-ol to give the hydrobromide salt which wasrecrystallised from propan-2-ol. The melting point of the salt is givenin Table AA.

AA15 The residue from the evaporation of the solvent from the reactionsolution was dried by azeotropic distillation with propan-2-ol,decolourised with charcoal in methanol and recrystallised frompropan-2-ol to give the hydrobromide salt, the melting point of which isgiven in Table AA.

AA16 The residue from the evaporation of the solvent from the reactionmixture was partitioned between water and dichloromethane. The organiclayer yielded the desired product.

AA17 The residue from evaporation of the solvent from the reactionmixture was partitioned between ethyl acetate and saturated aqueoussodium bicarbonate solution. The organic layer yielded a residue whichwas dissolved in a 10:1 mixture of ether and propan-2-ol and treatedwith ethereal HCl. The desired compound in the form of its hydrochloridesalt precipitated on cooling and was recrystallised from a 10:1 mixtureof propan-2-ol and methanol. The melting point of this salt is given inTable AA.

AA18 The residue from evaporation of the solvent from the reactionmixture was partitioned between ether and water. The organic layer wasseparated, decolourised with charcoal, evaporated to half volume andtreated with ethereal HCl to give the desired product as a hydrochloridesalt.

AA19 The residue from evaporation of the solvent from the reactionmixture was partitioned between ethyl acetate and saturated aqueoussodium bicarbonate solution. The organic phase was decolourised withcharcoal and the solvent removed to give a residue which was treatedwith ethanolic HCl to give the desired product as a hydrochloride saltwhich was recrystallised from acetone. The melting point of this salt isgiven in Table AA.

AA20 The residue from evaporation of the solvent from the reactionmixture was partitioned between ether and water and the dried etherlayer was treated with ethanolic HCl to give a gum which was treatedwith methanol to give the desired product as its hydrochloride saltwhich was used without further purification.

AA21 The residue from evaporation of the solvent from the reactionmixture was dried by azeotropic distillation with propan-2-ol, anddecolourised with charcoal in methanol. The solvent was removed and theresidue was treated with a mixture of propan-2-ol and ether to give asolid which was recrystallised from a 1:1 mixture of ethanol and etherto give the desired product as its hydrobromide salt, the melting pointof which is given in the last column of Table AA.

AA22 The residue from evaporation of the solvent from the reactionmixture was dried by azeotropic distillation with propan-2-ol to give aresidue which was crystallised from propan-2-ol to give the hydrobromidesalt of the desired compound of formula I, the melting point of which isgiven in the last column of Table AA.

AA23 The starting material was liberated from its hydrochloride saltprior to the reaction. The solvent was removed from the reaction mixtureand the residue was partitioned between ether and water. The ether layeryielded the desired product.

AA24 The residue from the reaction mixture was decolourised withcharcoal in methanol and partitioned between ether and saturated aqueoussodium bicarbonate solution. The ether layer yielded a residue which wastreated with ethereal HCl to give the hydrochloride salt. The meltingpoint of this salt is given in Table AA.

AA25 The reaction mixture was cooled and poured into water. The mixturewas extracted with ether. The desired product was obtained from theether extract.

AA26 The reaction mixture was poured onto ice and basified with 5Naqueous sodium hydroxide solution and extracted with ether. The etherextract gave a residue which was dissolved in ether. Treatment withethereal oxalic acid gave the oxalate salt of the desired product, themelting point of which is given in the last column of Table AA.

AA27 The solvent was removed from the reaction mixture and the residuepartitioned between water and ether. The residue from evaporation of theextracts was treated with ethereal HCl and propan-2-ol. Removal of thesolvents gave the hydrochloride salt of the desired product. The meltingpoint of this salt is given in the last column of Table AA.

AA28 The residue from the reaction mixture was treated with saturatedaqueous sodium bicarbonate colution and extracted with ethylacetate. Theextracts gave a residue which was treated with a 1:10 mixture ofpropan-2-ol and ethereal HCl to give the hydrochloride salt of thedesired product. The melting point of this salt is given in Table AA.

AA29 The solvent was removed from the reaction mixture and water addedto the residue. The resulting mixture was extracted with ether. Etherealoxalic acid was added to precipitate the oxalate salt of the product.The salt was dissolved in 1M aqueous sodium hydroxide solution andextracted with ether. The extract gave the desired product (as its freebase) which was used without further purification.

AA30 The solvent was removed from the reaction mixture and the residuedried by azeotropic distillation with propan-2-ol, decolourised withcharcoal in methanol and again dried by azeotropic distillation withpropan-2-ol. The residue was dissolved in propan-2-ol and a solidprecipitated by the addition of ether. This dissolution/precipitationcycle was repeated and the solid collected and washed with a 1:5 mixtureof propan-2-ol and ether to give the desired product as its hydrobromidesalt, the melting point of which is given in the last column of TableAA.

AA31 The residue from the reaction mixture was dried by azeotropicdistillation with propan-2-ol to give a residue which was decolourisedwith charcoal in methanol, to give the hydrobromide salt. The meltingpoint of the salt is given in Table AA.

                                      TABLE AA                                    __________________________________________________________________________    PART 1                                                                        Ex                                                                              OR.sub.3                                                                          R.sub.4                                                                           E   G       SM  a  b  c d  e  Note                                  __________________________________________________________________________    13                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.2                                                                  4-chlorophenyl                                                                        RB7 3.1                                                                              2.5                                                                              1.4                                                                             100                                                                              4  AA1                                   14                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.4                                                                  4-chlorophenyl                                                                        RB17                                                                              4.9                                                                              3.3                                                                              2 50 1  AA3                                   15                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.4                                                                  phenyl  RB8 8.1                                                                              6.5                                                                              3.7                                                                             100                                                                              1  AA5                                   16                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.5                                                                  4-chlorophenyl                                                                        RB9 9.1                                                                              6.5                                                                              3.7                                                                             200                                                                              0.75                                                                             AA5                                   17                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  4-bromophenyl                                                                         RC5 5  3.4                                                                              1.9                                                                             75 4  AA5                                   18                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  3,4-dichloro-                                                                         RB13                                                                              3.5                                                                              2.5                                                                              1.4                                                                             50 2  AA3                                                 phenyl                                                          19                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.4                                                                  4-hydroxy-                                                                            RB12                                                                              7  5.3                                                                              3 50 0.5                                                                              AA10                                                phenyl                                                          20                                                                              7-OMe                                                                             6-Br                                                                              (CH.sub.2).sub.3                                                                  phenyl  RB11                                                                              4.2                                                                              2.4                                                                              1.7                                                                             75 1.5                                                                              AA5                                   21                                                                              7-OMe                                                                             6-OMe                                                                             W   phenyl  RB10                                                                              10 7.9                                                                              4.2                                                                             100                                                                              1.5                                                                              AA13                                  22                                                                              7-OMe                                                                             6-Cl                                                                              (CH.sub.2).sub.3                                                                  2-chlorophenyl                                                                        RC6 3.6                                                                              2.8                                                                              1.6                                                                             50 1.5                                                                              AA13                                  23                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-trifluoro-                                                                          RC7 5  3.5                                                                              2 100                                                                              2  AA13                                                methylphenyl                                                    24                                                                              7-OMe                                                                             6-F (CH.sub.2).sub.3                                                                  2-chlorophenyl                                                                        RC8 5  4  2.3                                                                             75 16 AA13                                  25                                                                              7-OMe                                                                             6-F (CH.sub.2).sub.3                                                                  phenyl  RB14                                                                              8  7  4 100                                                                              1.5                                                                              AA13                                  26                                                                              5-OMe                                                                             H   (CH.sub.2).sub.3                                                                  4-chlorophenyl                                                                        RB15                                                                              4  3.4                                                                              1.9                                                                             75 3.5                                                                              AA16                                  27                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.2                                                                  phenyl  RB16                                                                              5  4.4                                                                              2.5                                                                             75 3  AA18                                  28                                                                              7-OMe                                                                             6-Cl                                                                              (CH.sub.2).sub.3                                                                  phenyl  RB18                                                                              5.6                                                                              4.9                                                                              2.8                                                                             50 1  AA20                                  29                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.5                                                                  phenyl  RB19                                                                              11 8.7                                                                              4.5                                                                             100                                                                              1.5                                                                              AA13                                  30                                                                              7-OMe                                                                             6-Cl                                                                              W   phenyl  RB21                                                                              2.1                                                                              1.6                                                                              0.9                                                                             30 1  AA23                                  31                                                                              6-OMe                                                                             7-Cl                                                                              (CH.sub.2).sub.3                                                                  phenyl  RB23                                                                              10.2                                                                             13.1                                                                             2.4                                                                             80 4  AA25                                  32                                                                              7-OMe                                                                             5-Cl                                                                              (CH.sub.2).sub.3                                                                  phenyl  RB24                                                                              7.1                                                                              5.4                                                                              3.1                                                                             100                                                                              0.5                                                                              AA27                                        6-OMe                                                                   33                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  3-chlorophenyl                                                                        RC21                                                                              9.1                                                                              7.3                                                                              4.1                                                                             75 2  AA29                                  34                                                                              7-OMe                                                                             6-F (CH.sub.2).sub.3                                                                  2-bromophenyl                                                                         RC19                                                                              5.1                                                                              3.6                                                                              2.1                                                                             100                                                                              2.5                                                                              AA13                                  __________________________________________________________________________    PART II                                                                       Ex  POS  R.sub.1                                                                           f     g h     j Note    mp                                       __________________________________________________________________________    13  7-OH 6-OH                                                                              2.25  30                                                                              0     5 AA2     227-229                                  14  7-OH 6-OH                                                                              5     50                                                                              0     2 AA4     228-232                                  15  7-OH 6-OH                                                                              5.9   50                                                                              0     1 AA6     225-230 (dec)                            16  7-OH 6-OH                                                                              7.5   30                                                                              0     1.5                                                                             AA7     231-233 (dec)                            17  7-OH 6-OH                                                                              4.0   20                                                                              20    6 AA8     208-211 (dec)                            18  7-OH 6-OH                                                                              3.9   30                                                                              0     0.5                                                                             AA9                                              19  7-OH 6-OH                                                                              3     50                                                                              0     0.5                                                                             AA11    194-196 (dec)                            20  7-OH 6-Br                                                                              3.6   20                                                                              20    3 AA12    205 (dec)                                21  7-OH 6-OH                                                                              10    25                                                                              25    5 AA4     200 (dec)                                22  7-OH 6-Cl                                                                              3.1   20                                                                              20    8 AA14    215-218                                  23  7-OH 7-OH                                                                              4.4   20                                                                              20    6 AA15    195 (dec)                                24  7-OH 6-F 3.9   25                                                                              25    2 AA15    212-215 (dec)                            25  7-OH 6-F 6.5   25                                                                              25    4 AA15    222-224 (dec)                            26  5-OH H   3.8   20                                                                              20    3.5                                                                             AA17    165-167                                  27  7-OH 6-OH                                                                              2.5   30                                                                              0     1 AA19    190-192                                  28  7-OH 6-Cl                                                                              5.6   25                                                                              22    24                                                                              AA21    205-208                                  29  7-OH 6-OH                                                                              10.8  50                                                                              25    5 AA22    >200 (dec)                               30  7-OH 6-Cl                                                                              2.0   10                                                                              10    3 AA24    >240 (dec)                               31  6-OH 7-Cl                                                                              5.9   80                                                                              0     5 AA26    105-109 (dec)                            32  7-OH 5-Cl                                                                              7.1   30                                                                              30    5 AA28    214-216                                           6-OH                                                                 33  7-OH 6-OH                                                                              7.8   30                                                                              30    5 AA30    225-230                                  34  7-OH 6-F 2.5   20                                                                              20    8 AA31    248 (dec)                                __________________________________________________________________________

EXAMPLES 35-39 ##STR27##

A mixture of a compound of formula VI in which OR₃, R₄, E and G are asidentified in Table AB Part I (a g), anhydrous potassium carbonate (bg), methyl iodide (c g) and acetone (d ml) was stirred at ambienttemperature for e hours. The mixture was filtered and the solventremoved to give a residue which was partitioned between ether and water.The ether layer yielded a compound of formula IV in which R₂ is methyland OR₃, R₄, E and G are as identified in Table AB Part I. This compoundof formula IV was then heated under reflux with a solvent identified incolumn f of Table AB Part II (a=methanol, b=ethanol) (g ml) andconcentrated hydrochloric acid (h ml) for j hours to give the desiredcompound of formula I in which the position of the hydroxy substituentis identified in the column headed "POS" in Table AB Part II, R₁ is asidentified in Table AB Part II, R₂ is methyl and E and G are asidentified in Table AB Part I. The procedure used to obtain the productis identified by the following notes to Table AB.

NOTES TO TABLE AB

The abbreviation "OBz" represents benzyloxy.

AB1 The solvent was removed from the reaction mixture and the residuepartitioned between saturated aqueous sodium bicarbonate solution andethyl acetate. The organic layer yielded a residue which was treatedwith ethereal oxalic acid to give the desired product as its oxalatesalt, which was recrystallised from acetonitrile. The melting point ofthe salt is given in the last column of Table AB.

AB2 The solvent was removed from the reaction mixture and the residuebasified with saturated aqueous sodium bicarbonate solution andextracted with ether. The extracts were treated with a 4:1 mixture ofethereal hydrogen chloride and propan-2-ol. Removal of the solvent gavea residue which was dried by azeotropic distillation with propan-2-ol.The residue was collected by filtration, washed with ether and dried invacuo at 60° C. to give the desired product as its hydrochloride salt,the melting point of which is given in the last column of Table AB.

AB3 The solvent was removed from the reaction mixture. The residue wasbasified with saturated aqueous sodium bicarbonate solution andextracted with ethyl acetate. The extract yielded a residue which wasdissolved in ether. Ethereal oxalic acid was added to give a solid whichwas boiled with a 9:1 mixture of ether and acetone to give the desiredproduct as its oxalate salt, the melting point of which is given in thelast column of Table AB.

AB4 The solvent was removed from the reaction mixture and the residuedecolourised with charcoal in ethanol and dried by azeotropicdistillation with propan-2-ol. The residue was triturated with ethylacetate and dissolved in ethanol. The solvent was removed and theresidue washed with petroleum ether (bp 60°-80° C.) and dried at 55° C.in vacuo to give the desired product as its hydrochloride salt, themelting point of which is given in the last column of Table AB.

AB5 Before heating the compound of formula IV under reflux, the compoundwas dissolved in a 1:1 mixture of ethyl acetate and petroleum ether (10ml) and eluted through a flash chromatography column using the samesolvent mixture as the eluant. Material having a retention factor (Rf)of 0.33 was collected and the solvent distilled off to give a solidwhich was dissolved in ethyl acetate and passed through a Florisil®column. Material having a retention factor (Rf) of 0.33 was collectedand the solvent distilled off to yield a gum. This was dissolved inether (60 ml), filtered and hydrogen chloride gas bubbled through thefiltrate until precipitation ceased. The solid was collected byfiltration, washed with ether and dried in vacuo at 50° C. for 4 hours(m.p. 173°-179° C.).

After heating the compound of formula IV under reflux, the solvent wasremoved from the reaction mixture and the residue dried by azeotropicdistillation with propan-2-ol. The residue was triturated with a 1:3mixture of propan-2-ol and ether and the solid collected by filtration,washed in a 1:3 mixture of propan-2-ol and ether and dried in vacuo at50° C. for 4hours to give the desired product as its hydrochloride salt,the melting point of which is given in the last column of Table AB.

                                      TABLE AB                                    __________________________________________________________________________    PART I                                                                        Ex                                                                              OR.sub.3                                                                          R.sub.4                                                                           E   G         SM  a b  c  d  e                                      __________________________________________________________________________    35                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-chlorophenyl                                                                          RB25                                                                              5 3.2                                                                              1.6                                                                              50 2                                      36                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.5                                                                  phenyl    RB26                                                                              5.5                                                                             3.6                                                                              2  100                                                                              3                                      37                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2,4-dichlorophenyl                                                                      RC13                                                                              3.8                                                                             2.2                                                                              1.3                                                                              75 1                                      38                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-methoxyphenyl                                                                         RC16                                                                              5.6                                                                             3.6                                                                              2  80 0.5                                    39                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  3-methoxyphenyl                                                                         RC17                                                                              5.4                                                                             4.35                                                                             2.15                                                                             70 3                                      __________________________________________________________________________    PART II                                                                       Ex POS   R.sub.1                                                                            f g     h j    Notes                                                                             mp                                           __________________________________________________________________________    35 7-OH  6-OMe                                                                              (a)                                                                             25    25                                                                              3    AB1 129-131                                      36 7-OH  6-OMe                                                                              (b)                                                                             30    30                                                                              3    AB2 135-140                                      37 7-OH  6-OMe                                                                              (a)                                                                             20    20                                                                              2.5  AB3 173-176                                      38 7-OH  6-OMe                                                                              (a)                                                                             25    25                                                                              5    AB4 130-135                                      39 7-OH  6-OMe                                                                              (b)                                                                             25    25                                                                              6    AB5 180-186                                      __________________________________________________________________________

EXAMPLE 40

Formic acid (39ml) was added dropwise at 0° C. under nitrogen to amixture of1-[]-(2-bromophenyl)cyclobutyl]-6-chloro-7-methoxy-3,4-dihydroisoquinoline(5.5 g prepared as described in Example CA20), sodium borohydride (3.9g) and tetrahydrofuran (50 ml). The reaction mixture was stirred atambient temperature for 16 hours. A further portion of sodiumborohydride (1 g) was added and the mixture heated at 50° C. for twohours. Water was added and the mixture basified by adding 50% aqueoussodium hydroxide. The mixture was extracted with ethyl acetate. Theextract yielded a residue which was purified by flash chromatography. Amixture of the purified residue (0.7 g), glacial acetic acid (10 ml),48% aqueous hydrobromic acid (10 ml) was heated under reflux for fivehours. The solvent was then removed and the residue treated withpropan-2-ol. Removal of the solvent gave1-[1-(2-bromophenyl)cyclobutyl]-6-chloro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide which was washed with ether and dried in vacuo, m.p.165°-170° C. (dec).

EXAMPLE 41

Sodium borohydride (a total of 8 g) was added portionwise to a warmmixture of 7-methoxy-1-(1-phenyl-cyclobutyl)-3,4-dihydroisoquinoline (15g prepared as described in Example CT13) and industrial methylatedspirits (200 ml) over a period of one hour. The mixture was added towater. The industrial methylated spirits were removed by evaporation andthe residue extracted with ether. Removal of the solvent gave an oilwhich was dissolved in acetone (250 ml) and stirred with methyl iodide(7.57 g) and anhydrous potassium carbonate (13.4 g) for one hour at50°-55° C. The reaction mixture was treated with charcoal and filtered.Removal of the solvent gave a residue which was digested with ether. Theether solution was filtered and the solvent removed to give an oil whichwas dissolved in glacial acetic acid (75 ml). 48% Hydrobromic acid (75ml) was added and the mixture heated under reflux for 4 hours. Thereaction mixture was added to a mixture of ice and aqueous ammoniasolution. A semi-solid was deposited. The supernatant liquors wereremoved by decantation and the residue washed with water and dissolvedin ethanol. Concentrated hydrochloric acid was added. The solvent wasremoved by evaporation to Give7-hydroxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinolinehydrochloride (m.p. 236°-240° C.) which was crystallised frompropan-2-ol.

EXAMPLE 42

A mixture of6,7-dimethoxy-1-[1-(2-naphthyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline(4.74 g prepared as described in Example RB20), 37-40% aqueousformaldehyde solution (5.1 ml), acetonitrile (120 ml) and sodiumcyanoborohydride (1.3 g) was stirred at ambient temperature for 15minutes. The mixture was neutralised by addition of glacial acetic acidand stirred for 45 minutes. The mixture was concentrated by evaporationand basified with 2N aqueous potassium hydroxide solution. The resultingmixture was extracted with ether. The extracts were washed with aqueouspotassium hydroxide solution and extracted with aqueous hydrochloricacid. The acid extract was basified and extracted with ether. The etherextract yielded a residue, a portion (3.86 g) of which was mixed with48% aqueous hydrobromic acid (40 ml) and glacial acetic acid (40 ml) andheated at 100° C. for two days. The solvent was removed by evaporationand the residue dried by azeotropic distillation with propan-2-ol. Theresidue was washed with ether and decolourised with charcoal inpropan-2-ol. The mixture was filtered and yielded6,7-dihydroxy-2-methyl-1-[1-(2-naphthyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline1.1 hydrobromide (m.p. 150°-153° C.) which was dried in vacuo.

EXAMPLE 43

1M Sodium hydrogen phosphite [179 ml, prepared from phosphorous acid(14.7 g), water (180 ml) and sodium hydrogen carbonate (15 g)], then37-40% aqueous formaldehyde solution (94 ml) was added to a stirredsolution of7-benzyloxy-6-methoxy-1-[1-(1-naphthyl)cyclopropyl]-1,2,3,4-tetrahydroisoquinoline(9.3 g, prepared as described in Example RC15) in industrial methylatedspirits (1 L). The mixture was stirred for 16 hours and the solventremoved in vacuo. Water (300 ml) was added to the residue, followed byexcess aqueous ammonia solution. The product was extracted into ether.The extracts yielded a residue (9.1 g) which was extracted with a warm5:4:1 mixture of petroleum ether (b.p. 40°-60° C.), ether andtriethylamine. The solvents were removed from the extract by evaporationand the residue was purified by flash chromatography, using the abovesolvent mixture as eluant to give7-benzyloxy-6-methoxy-2-methyl-1-[1-(1-naphthyl)-cyclopropyl]-1,2,3,4-tetrahydroisoquinoline as a gum.

The gum was heated under reflux with ethanol (16 ml) and concentratedhydrochloric acid (16 ml) for 30 minutes, the solvent removed in vacuoand the residue digested with cold water to give7-hydroxy-6-methoxy-2-methyl-1-[1-(1-naphthyl)cyclopropyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride (4.06 g), m.p. 196°-200° C.

EXAMPLE 44

A mixture of5-chloro-8-methoxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline(5.5 g) prepared as described in Example MI5), 48% aqueous hydrobromicacid (50 ml) and glacial acetic acid (50 ml) was heated under reflux ina nitrogen atmosphere for 24 hours. The solvents were removed byevaporation The residue was decolourised with charcoal in methanol. Themixture was filtered and the solvent removed from the filtrate. Theresidue was dried by azeotropic distillation with propan-2-ol, anddecolourised with charcoal in methanol. The mixture was filtered and thesolvent removed from the filtrate. The residue was dried by azeotropicdistillation with propan-2-ol and treated with ether to give5-chloro-8-hydroxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinolinehydrobromide, m.p. 197°-200° C. (dec).

EXAMPLE 45

A solution of 1-phenylcyclobutanecarbonyl chloride (29 g) in ether (100ml) was added to a mixture of 3,4-dimethoxyphenethylamine (28 g),triethylamine (25 ml) and ether (200 ml). The mixture was stirred for 1hour. The reaction mixture was poured into water and the mixtureextracted with ethyl acetate. The extract gave a solid (48.7 g) whichwas heated at 90°-95° C. for 64 hours with polyphosphate ester (200 g).The mixture was added to ice/water and the resulting mixture washed withether, basified with excess aqueous ammonia solution and extracted witha 1:1 mixture of ether and toluene and then with ethyl acetate. Removalof the solvents from the extracts gave a solid. A sample of this solid(40 g) in methanol (500 ml) was treated portionwise with sodiumborohydride (25 g in total). The mixture was heated under reflux for 16hours and then acidified with 6N aqueous hydrochloric acid, basifiedwith aqueous sodium hydroxide solution and extracted with ethyl acetate.The extract yielded a residue, a portion (15 g) of which was treateddropwise with formic acid (6.7 g) and then 37-40% aqueous formaldehydesolution (11 ml) was added. The mixture was heated under reflux for sixhours and then cooled and basified with 5N aqueous sodium hydroxidesolution. The resulting mixture was extracted with ether. The driedextract gave a residue which was dissolved in ether, filtered andtreated with ethereal HCl. Evaporation yielded a residue which wasrecrystallised from industrial methylated spirits to give6,7-dimethoxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinolinehydrochloride, m.p. 130°-132° C.

The free base of the above product (9 g) was heated under reflux with48% aqueous hydrobromic acid (200 ml) for 16 hours. On cooling a solidprecipitated which was collected, washed with water and decolourisedwith charcoal in industrial methylated spirits and filtered. Partialevaporation of the filtrate caused crystallisation of6,7-dihydroxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinolinehydrobromide, m.p. 95°-100° C.

EXAMPLE 46

A solution of methyl iodide (1.9 g) in acetone (20 ml) was addeddropwise to a stirred suspension of1-[1-(2,4-dichlorophenyl)cyclobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline(4 g prepared as described in Example RC9) and anhydrous potassiumcarbonate (3.1 g) in acetone (70 ml). The mixture was stirred at ambienttemperature for 90 minutes and the solvent removed by evaporation. Waterwas added and the mixture extracted with ether. The ether layer yielded1-[1-(2,4-dichlorophenyl)cyclobutyl]-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolineas an oil. A portion of this oil was characterised by conversion intoits 1.5 oxalate salt, m.p. 125°-132° C.

A solution of the oil (3.2 g obtained by the procedure of the precedingparagraph) in dichloromethane (50 ml) was cooled to -50° C. undernitrogen. A 1M solution of boron tribromide in dichloromethane (24 ml)was added dropwise. The mixture was stirred at ambient temperature for16 hours and cooled to -50° C. Methanol (20 ml) was added slowly. Thesolvents were removed by evaporation and the residue dried by azeotropicdistillation with propan-2-ol. The residue was decolourised withcharcoal in methanol and dissolved in propan-2-ol. Addition of ethercaused precipitation of1-[1-(2,4-dichlorophenyl)cyclobutyl-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide, m.p. 205°-210° C.

EXAMPLE 47

A solution of methyl iodide (0.5 g) in acetone (10 ml) was addeddropwise to a stirred suspension of1-[1-(2-chlorophenyl)cyclobutyl]-7-methoxy-1,2,3,4-tetrahydroisoquinolineoxalate (1.4 g prepared as described in Example RC11) and anhydrouspotassium carbonate (3 g) in acetone (80 ml). The mixture was stirred atambient temperature for 3.5 hours and the solvent removed byevaporation. Water was added and the mixture extracted with ether. Theether layer yielded1-[1-(2-chloro-phenyl)cyclobutyl]-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolineas an oil.

A solution of the oil (1.1 g obtained by the procedure of the precedingparagraph) in dichloromethane (50 ml) was cooled to -50° C. undernitrogen. A 1M solution of boron tribromide in dichloromethane (10 ml)was added dropwise. The mixture was stirred at ambient temperature for16 hours and cooled to -50° C. Methanol (20 ml) was added slowly. Thesolvents were removed by evaporation and the residue dried by azeotropicdistillation with propan-2-ol. The residue was decolourised withcharcoal in methanol, dissolved in propan-2-ol and the solution warmedto 35°-40° C. Addition of ether gave a solid which was triturated withwarm propan-2-ol. Ether was added to give1-[1-(2-chlorophenyl)cyclobutyl]-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide, m.p. 216°-218° C.

EXAMPLE 48

A finely divided mixture of 4-hydroxy-3-methoxyphenethylamine (9.9 g)and 1-phenylcyclopentane carboxylic acid (11.9 g) was heated at 200° C.under nitrogen for two hours. The melt was cooled slightly and added toa 1:1 mixture of glacial acetic acid and water. A solid crystallisedwhich was removed by filtration and washed with acetic acid. Thefiltrate was basified with excess sodium carbonate and extracted withether. The extract was washed with 4N hydrochloric acid. The etherextract yielded a residue which was heated under reflux in a nitrogenatmosphere with acetonitrile (156 ml) and phosphorus oxychloride (18.7ml) for one hour. The solvent was removed and water was added to theresidue. The mixture was warmed and ethanol was added. The resultingsolution was heated at 90°-95° C. for one hour and cooled. Ethanol wasadded to dissolve any solid and the solution basified with aqueousammonia solution. Sodium borohydride (2.5 g in total) was addedportionwise and the solvents removed by evaporation. The residue waspartitioned between water and ethyl acetate to give a solid which wascollected by filtration, washed with water and dried in air. The solidwas dissolved in a mixture of 37-40% aqueous formaldehyde solution (27ml) and formic acid (15 ml) and the solution warmed to 60° C. for twohours. Ice was added and the mixture basified with aqueous ammoniasolution. The resulting mixture was extracted with ether. The extractwas dried and the solvent removed to give a residue which was dissolvedin ether. The extract was filtered, dried and ethereal oxalic acid wasadded. A solid was deposited. The ether was removed by decantation andethyl acetate was added and the mixture heated at reflux. The solidproduct was triturated under the ethyl acetate, collected by filtrationwashed with ethyl acetate and dried in air to give7-hydroxy-6-methoxy-2-methyl-1-(1-phenylcyclopentyl-1,2,3,4-tetrahydroisoquinolineoxalate, m.p. 172° C. (dec).

EXAMPLE 49

A finely divided mixture of 4-hydroxy-3-methoxy phenethylamine (10.45 g)and 1-(4-chlorophenyl)cyclobutane carboxylic acid (12.17 g) was heatedat 200° C. under nitrogen for two hours. The melt was cooled and addedto a 1:1 mixture of glacial acetic acid and water. Addition of morewater caused a precipitate to be deposited which was extracted withether. The ether layer was washed with aqueous sodium carbonate solutionand then 6N hydrochloric acid and yielded a residue which was heatedunder reflux in a nitrogen atmosphere with acetonitrile (227 ml) andphosphorus oxychloride (27.2 ml) for 16hours. Water (50 ml) andindustrial methylated spirits were added and the mixture heated for 1hour. After 16 hours excess aqueous ammonia solution and ice were addedand the resulting solid was collected and washed with water and etherand dried at 60° C. in vacuo. The residue was digested with ethanol andthe insoluble solid collected and dissolved in methanol (250 ml) andwater (50 ml). Sodium borohydride (a total of 2.8 g) was addedportionwise. The mixture was warmed for 30 minutes and then water andexcess dilute hydrochloric acid were added. The supernatant liquor wasbasified with aqueous ammonia solution and the resultant precipitateextracted with ether. The ether was removed to leave a residue which waswarmed with a mixture of 37-40% aqueous formaldehyde solution (45 ml)and formic acid (27 ml) for one hour. The mixture was allowed to standfor 16 hours and was then heated for a further 30 minutes and cooled.Ice and excess aqueous ammonia solution were added and the resultingmixture was extracted with ether. The solvent was removed and theresidue dissolved in ether. Ethereal oxalic acid solution was added tothe dried solution to give a semi-solid which was triturated withboiling ether and digested with ethyl acetate to give a gum which wasdigested with propan-2-ol to give1-[1-(4-chlorophenyl)cyclobutyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolineoxalate, m.p. 202° C. (dec).

EXAMPLE 50

A solution of 1-(4-chlorophenyl)cyclobutanecarbonyl chloride (22.9 g) inether (200 ml) was added to a stirred mixture of3,4-dimethoxyphenethylamine (18.1 g), triethylamine (13.9 ml) and ether(300 ml). The mixture was stirred for 1.5 hours and then water wasadded. The ether layer yielded a residue which was dissolved indichloromethane (100 ml) and added to polyphosphate ester (195 g) undernitrogen. The mixture was kept at 75°-82° C. for 16 hours and then addedto water (1,200 ml). The organic phase was washed with water andbasified with excess aqueous ammonia solution. The basic aqueoussolution was extracted with ether. The ether extract yielded an oilwhich was dissolved in methanol (200 ml). Twelve portions of sodiumborohydride (12 g in total) were added over twenty minutes. The mixturewas stirred for 16 hours and acidified by the careful addition of 5Nhydrochloric acid. The mixture was allowed to stand for 16 hours and theresulting solid was separated by filtration. Water was added to thefiltrate which was then basified and extracted with ethyl acetate. Theextract gave a residue which was dried by azeotropic distillation withpropan-2-ol to give1-[1-(4-chlorophenyl)cyclobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline,a sample (8.8 g) of which was heated at 90°-95° C. with formic acid (5ml) and 37-40% aqueous formaldehyde solution (6.2 ml) for 16 hours.Water was added and the mixture basified with aqueous sodium hydroxidesolution and extracted with ether. The extract yielded a gum which washeated under reflux with 48% aqueous hydrobromic acid (100 ml) for 31/2hours. Charcoal and industrial methylated spirits (100 ml) were addedand the mixture filtered. Removal of the solvent from the filtrate gavea residue which was dried by azeotropic distillation with propan-2-ol.The residue was taken up in a 1:1 mixture of propan-2-ol and ethanol andthe solvent removed by evaporation. The residue was heated under refluxwith ethanol for 30 minutes and then cooled. The solid was collected byfiltration and washed with a small amount of cold ethanol to give1-[1-(4-chlorophenyl)cyclobutyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide, m.p. 220° C.

EXAMPLE 51

A solution of 1-(4-chlorophenyl)cyclobutane carbonyl chloride (30.7 g)in ether (300 ml) was added to a stirred solution of4-methoxyphenethylamine (20.2 g) and triethylamine (20 ml) in ether (200ml). After one hour, water (200 ml) was added and the ether layerremoved by decantation. The aqueous layer was extracted withdichloromethane. The combined organic extracts gave a residue (46 g)which was mixed with polyphosphate ester (110 ml) and heated on a steambath for 65 hours. The reaction mixture was added to a mixture of iceand concentrated aqueous ammonia solution and extracted with ether andethyl acetate. The combined organic extracts gave a residue which wasdissolved in ethanol (180 ml). Sodium borohydride (15.6 g in total) wasadded portionwise. The mixture was heated for one hour at 90°-95° C.Water and then dilute hydrochloric acid were added and the mixturebasified with aqueous sodium hydroxide solution and extracted withether. The extract was cooled, filtered and ethereal oxalic acid addedto give a gum which was triturated with ether. The residue was basifiedwith aqueous potassium hydroxide solution to give a residue which waspurified by high performance liquid chromatography and a portion (1.6 g)of the product was heated under nitrogen for 19 hours with glacialacetic acid (35 ml) and 48% hydrobromic acid (35 ml). The mixture wascooled and added to a mixture of ice and 10% aqueous sodium carbonatesolution. The insoluble material which was deposited was decolourisedwith charcoal in a mixture of 6N hydrochloric acid, acetic acid andmethanol. The solution yielded a residue which was dried by azeotropicdistillation with propan-2-ol.

A mixture of the residue (1 g), sodium formate (0.2 g), 37-40% aqueousformaldehyde solution (10 ml) and formic acid (10 ml) was heated at90°-95° C. for 20 minutes. The mixture was allowed to stand for 16 hoursand was poured onto a mixture of ice and aqueous ammonia solution whichwas extracted with ether. The extract yielded a residue which waspurified by flash chromatography and converted into1-[1-(4-chlorophenyl)cyclobutyl]-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline1.35 oxalate, m.p. 192°-194° C. (dec).

EXAMPLE 52

1-Phenylcyclobutanecarbonyl chloride (20 g) in ether (100 ml) was addedto a stirred mixture of 3-chloro-4-methoxyphenethylamine (19.1 g),triethylamine (14 ml) and ether (100 ml) and the resulting mixturestirred for one hour. Water was added and the mixture extracted withethyl acetate. The extract yielded a solid (m.p. 62°-64° C.), a sampleof which (14.6 g) was heated at 90° C. with polyphosphate ester (89 ml)for 48 hours. The mixture was poured into ice/water, basified withaqueous ammonia solution and extracted with ether. A portion (90% of thetotal) of the extract was added to a mixture of sodium borohydride (6 g)and ethanol (400 ml). The mixture was heated under reflux for 90 minutesafter the ether had been allowed to escape and then the solvent wasremoved by evaporation to give a residue which was added to water. Theresulting mixture was extracted with ether. The ether extract was addedto a mixture of 1M aqueous sodium phosphite solution [prepared fromphosphorous acid (20.5 g), sodium bicarbonate (21.0 g) and water (250ml)], 37-40% aqueous formaldehyde solution (150 ml) and methanol (400ml). The mixture was heated under reflux for 17 hours allowing the etherto evaporate. The methanol was then removed by evaporation and theresidue basified with aqueous ammonia solution and extracted with ether.The extract yielded an oil which was purified by flash chromatographyand then high performance liquid chromatography to give a compound (4.1g) which was heated under reflux for five hours with glacial acetic acid(45 ml) and 48% hydrobromic acid (45 ml). The cooled reaction mixturewas partitioned between ether and 50% aqueous potassium carbonatesolution. The extract yielded a glass which was dissolved in ether andtreated with ethereal oxalic acid to give 6-chloro-7-hydroxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinolineoxalate (m.p. 220°-223° C.).

EXAMPLE 53

A solution of 1-(4-chlorophenyl)cyclobutanecarbonyl chloride (20 g) inether (50 ml) was added to a stirred mixture of3-chloro-4-methoxyphenethylamine (16.2 g), triethylamine (13 ml) andether (100 ml). After one hour, water (50 ml) was added and the mixtureextracted with ethyl acetate. The organic layer gave a residue which wasrecrystallised twice from industrial methylated spirits. A portion ofthe product (12.6 g) was warmed with polyphosphate ester (70 ml). Theresulting solution was heated at 90° C. for 48 hours, cooled and addedto a mixture of ice, concentrated ammonia solution and ether. The etherlayer was washed, dried and added to sodium borohydride (5 g) in ethanol(200 ml) and the mixture heated under reflux for 90 minutes. The etherevaporated during this time and then the ethanol was removed. Water (200ml) was added and the resulting mixture extracted with ether. Theextract was added to a mixture of 1M aqueous sodium phosphite solution[prepared from phosphorous acid (16.4 g), sodium bicarbonate (16.8 g)and water 200 ml)], 37-40% aqueous formaldehyde solution (130 ml) andmethanol (300 ml). The ether was removed by evaporation and methanol(250 ml) added. The mixture was then heated under reflux for 16 hoursand then the methanol was removed by evaporation. The residue wasbasified with aqueous ammonia solution and extracted with ether. Thesolvent was removed from the extract and the residue dried by azeotropicdistillation with industrial methylated spirits and then withpropan-2-ol. The dried residue was crystallised from propan-2-ol to givea solid which was further purified by high performance liquidchromatography. A sample of this purified product (1 g) was heated at110°-115° C. under nitrogen with glacial acetic acid (10 ml) and 48%hydrobromic acid (10 ml) for 6 hours. The reaction mixture was thencooled and partitioned between ether and 50% aqueous potassium carbonatesolution. The ether layer yielded6-chloro-1-[1-(4-chlorophenyl)cyclobutyl]-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(m.p. 168°-171° C.).

EXAMPLE 54

A solution of 1-(4-methoxyphenyl)cyclobutanecarbonyl chloride (5.83 gprepared as described in Example CL28) in dichloromethane (20 ml) wasadded to a solution of 3,4-dibenzyloxyphenethylamine hydrochloride (9.61g) in dichloromethane (100 ml). Triethylamine (20 ml) was added. After16 hours the mixture was acidified with dilute hydrochloric acid. Theorganic layer yielded a residue which was heated under reflux for 3hours with phosphorus oxychloride (20 ml) and acetonitrile (200 ml).Removal of the solvent gave a residue which was digested with ethylacetate. On cooling a solid dichlorophosphate salt precipitated. Asample (11.6 g) of this salt was added portionwise to a stirred mixtureof sodium borohydride (9.5 g) in industrial methylated spirits (250 ml).The reaction mixture was heated for 3 hours at 90°-95° C. A mixture ofsodium borohydride (3 g) and industrial methylated spirits (150 ml) wasadded and the resulting mixture gently boiled for two hours. The volumeof the reaction mixture was reduced, water was added and the resultingmixture extracted with ether. The ether extract yielded a residue whichwas dissolved in a mixture of methanol (190 ml) and 37-40% aqueousformaldehyde solution (65 ml). The resulting solution was mixed with 1Maqueous sodium phosphite solution [prepared from phosphorous acid (9.9g), sodium bicarbonate (10.1 g) and water (120 ml)] and methanol (300ml) was added. The mixture was warmed and allowed to stand for 16 hours.The supernatant liquid was basified with aqueous ammonia solution andextracted with ether. The extract yielded a gum which was dissolved in amixture of methanol (100 ml) and formic acid (20 ml) and stirred undernitrogen with 5% palladium on charcoal (4 g Type 38H ex Johnson Matthey)for 3 hours. The mixture was filtered and concentrated hydrochloric acid(1.2 ml) added to the filtrate. The solvent was removed by evaporationand the residue dried by azeotropic distillation with propan-2-ol, amixture of propan-2-ol and toluene and then with propan-2-ol to give asolid which was triturated with ethyl acetate, collected by filtration,washed with ethyl acetate and dried in vacuo to give6,7-dihydroxy-1-[1-(4-methoxyphenyl)cyclobutyl-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrochloride, m.p. 85°-90° C.

EXAMPLE 55

Sodium borohydride (7 g in total) was added portionwise over 2.5 hoursto a solution of the product of Example CT15(25 g) in industrialmethylated spirits (300 ml) which was being heated under reflux. Waterwas added and the mixture extracted with ether. The extract yielded asolid which was mixed with a mixture of methanol (400 ml) and 37-40%aqueous formaldehyde solution (213 ml). A 1M solution of sodiumphosphite [prepared from phosphorous acid (33.6 g) and sodiumbicarbonate (34.4 g) and water (410 ml)] was added and the mixtureheated at 90°-95° C. for 4 hours. The volume of the reaction mixture wasreduced and the mixture basified with aqueous ammonia solution andextracted with ether. The extract yielded an oil which was dissolved inethanol (270 ml) and heated under reflux in a nitrogen atmosphere for 30minutes with concentrated hydrochloric acid (270 ml). The mixture wascooled and added to a mixture of ice and aqueous ammonia solution whichwas extracted with ether. The extract gave a residue which was purifiedby flash chromatography on silica using a 4:96 mixture of methanol anddichloromethane as eluant. The fraction containing the desired productwas treated with ethereal oxalic acid solution to give a gum which wascrystallised from a mixture of methanol and ethyl acetate to give-hydroxy-6-methoxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline1.4 oxalate (m.p. 132°-133° C.).

EXAMPLE 56

A solution of 2'-bromo-4',5'-dimethoxyphenylacetonitrile (136.8 g) and1,3-dibromopropane (58.7 ml) in dimethylsulphoxide (300 ml) was addeddropwise over 2 hours to a stirred mixture of powdered potassiumhydroxide hemihydrate (150 g) and 18-Crown-6(2 g) in dimethylsulphoxide(700 ml) under nitrogen at 24°-25° C. Stirring was continued for afurther two hours and then a mixture of water and ice was added. Theresulting mixture was extracted with dichloromethane. The extract gave aresidue which was crystallised from ether. A sample of this crystallisedmaterial (67.2 g) was heated under reflux with a solution of potassiumhydroxide hemihydrate (32.5 g) in propanol (600 ml) for 7 days. Thesolvent was removed and the residue partitioned between water and ethylacetate. The ethyl acetate layer yielded1-(2-bromo-4,5-dimethoxyphenyl)cyclobutane carboxamide which was heatedunder reflux with potassium hydroxide (30 g) and water (300 ml) for 3days. The mixture was washed with ethyl acetate and the aqueous layeracidified and extracted with ether. The resulting acid was dissolved inethyl acetate (80 ml) and the solution was mixed with a solution of4-benzyloxy-3-methoxyphenethylamine (10.8 g) in ethyl acetate (320 ml).A salt precipitated which was heated under nitrogen at 195° C. for 2hours and at 205° C. for 30 minutes. The reaction mixture was cooled andthe resulting glass was heated under reflux with phosphorus oxychloride(22 ml) and acetonitrile (200 ml) for 4 hours. The reaction mixture wasadded to a mixture of ice and aqueous ammonia solution. The mixture wasextracted with ether. The ether extract yielded a residue, a sample ofwhich (5.9 g) was digested with ether. Addition of ethereal oxalic acidsolution gave a solid which was basified with a methanolic solution ofpotassium hydroxide and partitioned between water and ether. The etherlayer yielded a residue which was purified by flash chromatography togive a gum which was stirred with glacial acetic acid (20 ml) andmethanol (10 ml) at 0° C. under nitrogen whilst sodium cyanoborohydride(0.8 g in total) was added portionwise. The mixture was then stirred at20°-25° C. for 16 hours, added to aqueous potassium hydroxide solutionand extracted with ether. The extract gave a residue (3.1 g) which wasmixed with methanol (300 ml), 37-40% aqueous formaldehyde solution (26ml) and 1M aqueous sodium phosphite solution [prepared from phosphorousacid (4.05 g), sodium bicarbonate (4.1 g) and water (50 ml)] and themixture allowed to stand for 3 days. The solvent was removed byevaporation in vacuo at less then 50° C. and the residue added to amixture of ice and aqueous ammonia solution and extracted with ether.The extract gave a residue which was dissolved in ethanol (35 ml) andwas treated under nitrogen with concentrated hydrochloric acid (35 ml).The mixture was boiled for 30 minutes, cooled, added to a mixture of iceand aqueous ammonia solution and extracted with ethyl acetate. Theextract gave a residue which was purified by flash chromatography togive1-[1-(2-bromo-4,5-dimethoxyphenyl)cyclobutyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline,m.p. 154°-157° C.

EXAMPLE 57

The product of Example 41 (4 g) was dissolved in water at 80° C. Thesolution was basified with aqueous ammonia solution and extracted withethyl acetate. The extract gave a residue which was dissolved in aceticacid (40 ml). The solution was cooled to 0° C. and acetic anhydride (20ml) and then a mixture of 70% nitric acid (1.4 ml), acetic acid (30 ml)and acetic anhydride (20 ml) were added. The mixture was kept at 5° C.for 40 minutes and was then added to aqueous sodium bicarbonate and leftfor 16 hours before being extracted with ethyl acetate. The extract gavea residue which was purified by flash chromatography to give a solidwhich was dissolved in ethyl acetate. Addition of ethereal oxalic acidsolution gave a solid which was triturated with hot ethyl acetate togive7-hydroxy-2-methyl-6-nitro-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinolineoxalate, m.p. 172°-173° C. (dec).

EXAMPLE 58

Sodium hypochlorite solution (11 ml--8% available chlorine) was added at0° C. to a mixture of the product of Example 41 in the form of its freebase (2 g), glacial acetic acid (25 ml), water (20 ml) and concentratedhydrochloric acid (20 ml). Glacial acetic acid (25 ml) and concentratedhydrochloric acid (20 ml) were added followed by a further amount (8 ml)of the above sodium hypochlorite solution. The mixture was stirred for20 minutes and excess solid sodium metabisulphite added. The mixture wasbasified with aqueous sodium hydroxide solution and extracted withether. The extract gave a residue which was dissolved in ether. Additionof ethereal oxalic acid solution gave6,8-dichloro-7-hydroxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline 1.5 oxalate, m.p. 120° C. (dec) .

EXAMPLE 59

A solution of 1-phenylcyclobutanecarbonyl chloride (19.45 g) indichloromethane (100 ml) was added at 10°-13° C. to a solution of3-chloro-4-methoxyphenethylamine (18.55 g) and triethylamine (30 ml) indichloromethane (300 ml) over 20minutes. The mixture was stirred at20°-25° C. for 3hours and stood for 3 days. Water was added and theorganic layer separated and washed with 2N hydrochloric acid and thenwith 1N aqueous sodium hydroxide solution. The organic layer gave a gum(32.89 g) which was heated under reflux with xylene (390 ml) andphosphorus oxychloride (76.8 ml) for ten hours. The reaction mixture wasadded portionwise to a stirred mixture of aqueous potassium hydroxidesolution and ice. The temperature was maintained below 85° C. Toluene ataround 80° C. was added to dissolve deposited oil. The organic layer wasseparated and yielded an oil which was crystallised from propan-2-ol.The crystallised solid (10 g) was dissolved in ethanol (200 ml) andsodium borohydride (2 g) added with warming. After 40 minutes thesolvent was removed and the residue treated with water and extractedwith ether to give a residue which was heated under reflux with sodiumborohydride (a total of 8 g) and propan-2-ol (100 ml) for a total of 7hours. The mixture was cooled and water, then dilute hydrochloric acidand then aqueous sodium hydroxide solution were added. The mixture wasextracted with ether. The ether extract gave6-chloro-7-methoxy-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinolinea portion of which (8.78 g) was dissolved in methanol (100 ml) andtreated with a solution of dibenzoyl-L-tartaric acid (10.08 g) inmethanol (50 ml). Solvent was removed at 40° C./40 mm Hg to leave 70 ml.Ether was added until a slight precipitate was seen and the mixturewarmed to give a clear solution. On cooling a solid precipitated whichwas separated by filtration. The filtrate was basified with aqueoussodium hydroxide solution and extracted with ether. The extract gave anoil which was treated in methanol with dibenzoyl-D-tartaric acid (7.12g) and a solid precipitated by the addition of ether. A sample of thelatter solid (2.9 g) and sodium bicarbonate (0.35 g) in methanol (50 ml)was stirred and 1M sodium phosphite solution [prepared from phosphorousacid (2.55 g), sodium bicarbonate (2.61 g) and water (31 ml)] and 37-40%aqueous formaldehyde solution (16 ml) was added. Methanol (50 ml) wasadded and the mixture left for 16 hours, basified with aqueous ammoniasolution and extracted with ether. The extract gave a residue which wasdissolved in glacial acetic acid (20 ml) and 48% hydrobromic acid (20ml) was added under nitrogen. The mixture was heated at 100° C. for 16hours and then under reflux for 6.5 hours, cooled, added to a mixture ofice and aqueous ammonia solution and extracted with ethyl acetate. Theextract gave a residue which was purified by flash chromatography togive(-)-6-chloro-7-hydroxy-2-methyl-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline(m.p. 73°-75° C.) which had a specific optical rotation α_(D) of-139.8°.

EXAMPLE 60

1-[1-(2-Bromophenyl)cyclobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroquinoline(15.7 g, prepared in a similar manner to that described in Example RB1)was dissolved in ether (1100 ml) and treated with a 0.4M solution ofdibenzoyl-L-tartaric acid in ether (98 ml). A solid precipitated whichwas collected by filtration and dried in vacuo. A portion of this solid(10.5 g)was dissolved in boiling methanol (350 ml). The solution wasallowed to stand for 2days and(-)-1-[1-(2-bromophenyl)cyclobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinedibenzoyl-L-tartrate, was collected by filtration and recrystallisedfrom methanol. Further samples of this salt were obtained from themother liquors from which the solid had precipitated by removing thesolvent by evaporation and recrystallising the residue from methanol.The salt (m.p. 174°-175° C. (dec)) had a specific optical rotation α_(D)of -57.6° to -61.9°.

A mixture of(-)-1-[1-(2-bromophenyl)cyclobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline(1.85 g) [liberated from the dibenzoyl-(L)-tartrate salt (3.7 g)],acetonitrile (60 ml), 37-40% aqueous formaldehyde solution (1.8 ml) andsodium cyanoborohydride (0.46 g) was stirred for 15 minutes, thenneutralised with glacial acetic acid and stirred for a further 45minutes. The mixture was concentrated by evaporation and basified to pH12 with dilute aqueous sodium hydroxide solution. The mixture wasextracted with ethyl acetate, the extract yielding a gum which waspurified via flash chromatography using a 1:2 mixture of ethyl acetateand petroleum ether as eluant to give(-)-1-[1-(2-bromophenyl)cyclobutyl]-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline,which had a specific optical rotation α_(D) of -33.6°. Yield 1.6 g.

A mixture of(-)-1-[1-(2-bromophenyl)cyclobutyl]-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(1.46 g), 48% aqueous hydrobromic acid (20 ml) and glacial acetic acid(20 ml) was heated under reflux for 5 hours. The solvent was removed byevaporation and the residue dried by repeated azeotropic distillationwith propan-2-ol. The residue was dissolved in propan-2-ol andprecipitated with ether. The resulting solid was dried in vacuo at 45°C. to yield (+)-1-[1-(2-bromo-phenyl)cyclobutyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide[m.p. 207°-209° C. (dec)] which had a specific optical rotation α_(D) of+38.2°.

EXAMPLE 61

A solution of 1-(2-chlorophenyl)cyclopropane carbonyl chloride (25 g) indichloromethane (100 ml) was added dropwise to a vigorously stirredmixture of 2-(3-fluoro-4-methoxyphenyl)ethylamine hydrochloride (23.9g), triethylamine (70 ml) and dichloromethane (400 ml) and the mixturewas then stirred for 1 hour. Excess 6N hydrochloric acid was then added.The resulting solution was washed with water, dried over potassiumcarbonate, and the solvent removed in vacuo to giveN-[2-(3-fluoro-4-methoxyphenyl)ethyl]-1-(2-chlorophenyl)cyclopropanecarboxamide which was added molten to polyphosphate ester (365 g) undernitrogen. The mixture was heated at 100° C. for 17 hours, then added towater (600 ml) and washed with ether (600 ml). 20% Aqueous ammoniasolution was added to the aqueous phase to give pH 8-9.The resultingprecipitate was collected by filtration, washed with water, dried in airand recrystallised from boiling acetonitrile to give1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-3,4-dihydroisoquinoline, m.p. 172°-176° C.

Sodium cyanoborohydride (10.7 g) was added at 0° C. to a mixture of1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-3,4-dihydroisoquinoline(26.7 g, prepared in a similar manner to that described above), aceticacid (185 ml) and methanol (95 ml) under nitrogen. The mixture wasallowed to reach ambient temperature and was stirred for 22 hours. Themixture was poured onto water, and solid sodium hydroxide (150 g) inice-water (500 ml) was added. The product was extracted into ether andthe solvent then removed in vacuo to yield1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-1,2,3,4-tetrahydroisoquinolineas a gum.

A mixture of the gum, methanol (2700 ml), 1M sodium hydrogen phosphite[690 ml, prepared from phosphorous acid (56.6 g) and sodium hydrogencarbonate (57.9 g)] and 37-40% aqueous formaldehyde solution (360 ml)was warmed to 60° C. and then stirred at ambient temperature for 64hours. The methanol was removed in vacuo, and a solution of potassiumhydroxide (50 g) in water (500 ml) and then ethyl acetate (500 ml) wereadded to the resulting aqueous suspension. The organic layer was driedover potassium carbonate and the solvent removed in vacuo to give a gumwhich was crystallised from acetonitrile to give1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.Yield 18.15 g.

A mixture of1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(18.0 g) in acetic acid (150 ml) and 48% aqueous hydrobromic acid (150ml) was heated under reflux under argon for 220 minutes. The solvent wasremoved in vacuo, and the residue dried by azeotropic distillation withpropan-2-ol and crystallised from propan-2-ol to yield1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide (18.56 g), m.p. 240° C. (dec).

EXAMPLE 62

1-[1-(2-Chlorophenyl)cyclopropyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide (18 g, prepared in a similar manner to that described inExample 61) was partitioned between aqueous ammonia solution and ethylacetate. The ethyl acetate was removed in vacuo and the residueseparated into two fractions by chiral preparative high performanceliquid chromatography on a Chiralcel OD column eluted with a 97:3mixture of hexane and ethanol. Fraction 1 was dissolved in propan-2-oland treated with a slight excess of 48% aqueous hydrobromic acid. Theresulting solid was collected by filtration and dried to give(+)-1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide which had a specific optical rotation α_(D) of +2.38°.Yield 7.88 g, m.p. 250° C. (dec).

EXAMPLE 63

A solution of1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide (1 g, prepared in a similar manner to that described inExample 61) in ethyl acetate (30 ml) was mixed with a solution of maleicacid (0.24 g) in ethyl acetate (8 ml) and the mixture warmed to form asolution. The solution was cooled to yield1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinemaleate, m.p. 183°-184° C. Yield 0.9 g.

EXAMPLE 64

1-[1-(2-Chlorophenyl)cyclobutyl]-6-fluoro-7-hydroxy-2methyl-1,2,3,4-tetrahydroisoquinoline(8.0 g liberated from the salt prepared as described in Example 24) wasresolved by chiral preparative high performance liquid chromatography ona Chiralcel OD column eluted with an 80:20 mixture of hexane andethanol. The residue formed by the removal of the solvent from fraction1 was dissolved in propan-2-ol and treated with 48% aqueous hydrobromicacid to yield(+)-1-[1-(2-chlorophenyl)cyclobutyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide which had a specific opticalrotation α_(D) of +9.64° , m.p. 242°-245° C. (dec). Yield 3.63 g.

EXAMPLE 65

6-Chloro-7-methoxy-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline(1.38 g prepared in a similar manner to that described in Example 59)which was dissolved in acetone (50 ml) and stirred with anhydrouspotassium carbonate (1.16 g) and allyl iodide (0.78 g) for one hour. Themixture was filtered and the filtrate concentrated and partitionedbetween water and ether. The ether layer yielded an oil which was takenup in dichloromethane (30 ml) and cooled to -70° C. A 1M solution ofboron tribromide in dichloromethane (11 ml) was added dropwise and themixture allowed to warm to ambient temperature. After two hours themixture was cooled to -60° C. and methanol (30 ml) was added cautiously.The solvents were removed and the residue decolourised with charcoal inmethanol. Removal of the solvent gave a residue which was recrystallisedfrom a mixture of propan-2-ol and ether to give 2-allyl-6-chloro-7-hydroxy-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinolinehydrobromide, m.p. 194°-196° C.

EXAMPLE 66

A mixture of1-[1-(4-chlorophenyl)cyclobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline(7.29 g prepared as described in Example 50), ethyl iodide (1.76 ml),anhydrous potassium carbonate (5.52 g) and acetone (100 ml) was heatedunder reflux for 16 hours. The reaction mixture was filtered and thesolvent was removed by evaporation to give a residue which was digestedwith a 9:1 mixture of petroleum ether and triethylamine. The solutionwas filtered and the solvent removed to give a residue. A sample of thisresidue (4 g) was heated under reflux in a nitrogen atmosphere withglacial acetic acid (40 ml) and 48% hydrobromic acid (40 ml) for 20hours. Removal of the solvent gave a residue which was dried byazeotropic distillation with industrial methylated spirit, then withpropan-2-ol and finally with a mixture of toluene and propan-2-ol togive a solid which was washed with propan-2-ol and dried in vacuo at 80°C. to give1-[1-(4-chlorophenyl)cyclobutyl]-2-ethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolinehydrobromide, m.p. 213°-215° C.

EXAMPLE 67

A mixture of1-[1-(4-chlorophenyl)cyclobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline(7.29 g prepared as described in Example 50), allyl bromide (2.66 g),anhydrous potassium carbonate (5.52 g) and acetone (100 ml) was heatedunder reflux for 2 hours. The reaction mixture was filtered and thesolvent was removed by evaporation to give a residue which was digestedwith a 9:1 mixture of petroleum ether and triethylamine. The solutionwas decanted from a residual tar, filtered and the solvent removed togive a residue. A sample of this residue (3 g) was heated under refluxin a nitrogen atmosphere with glacial acetic acid (50 ml) and 48%hydrobromic acid (50 ml) for 7 hours. The reaction mixture was added toice/water and excess aqueous ammonia solution added slowly undernitrogen. The resulting mixture was extracted with ethyl acetate. Theorganic layer was evaporated and the residue dissolved in ethyl acetate.Addition of a solution of oxalic acid in ethyl acetate gave2-allyl-1-[1-(4-chlorophenyl)cyclobutyl]-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolineoxalate [m.p. 85° C. (dec)] which was dried in air.

EXAMPLE 68

1-(2-Bromophenyl)cyclobutanecarbonyl chloride (9.4 g) was added to asolution of 4-benzyloxy-3-methoxy phenethylamine (8 g) and triethylamine(3.15 g) in ethyl acetate (50 ml) and tetrahydrofuran (50 ml). Themixture was stirred for two days, 2M aqueous potassium hydroxidesolution (50 ml) added and the mixture stirred for 20 minutes. Theaqueous layer was separated and extracted with ethyl acetate. Theextract was washed with 1M hydrochloric acid and brine and yielded anoil which was dissolved in acetonitrile (180 ml). Phosphorus oxychloride(12 ml) was added and the mixture heated under reflux for 2.5 hours. Themixture was cooled and added to a mixture of concentrated aqueousammonia solution (100 ml) and water (100 ml) and the mixture stirred for10 minutes and extracted with ethyl acetate. The extract yielded an oilwhich was triturated with ether and the resulting solid recrystallisedfrom cyclohexane to give7-benzyloxy-1-[1-(2-bromophenyl)cyclobutyl]-6-methoxy-3,4,-dihydroisoquinoline(m.p. 115°-116° C.). A sample (3.1 g) of this material in methanol (16ml) and acetic acid (35 ml) was treated with sodium cyanoborohydride (1g). The mixture was stirred for 16 hours, diluted with water, basifiedwith 50% aqueous sodium hydroxide solution and extracted with ether. Theextract gave a residue which was dissolved in acetonitrile (115 ml) andthen 37-40% aqueous formaldehyde solution (3.2 ml) and sodiumcyanoborohydride (0.83 g) were added. The mixture was stirred for 15minutes and then neutralised with acetic acid and stirred for 45minutes. After concentration, 2M aqueous sodium hydroxide solution wasadded and the mixture extracted with ethyl acetate. The extract gave7-benzyloxy-1-[1-(2-bromophenyl)cyclobutyl]-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline,a sample of which (3 g) was mixed with ethanol (70 ml) and concentratedhydrochloric acid (70 ml) and the mixture heated under reflux for 45minutes. The solvent was removed by evaporation and the residue dried byazeotropic distillation with propan-2-ol. The dried residue wassuspended in propan-2-ol (20 ml) and the mixture filtered. The filtratewas decolourised with charcoal in methanol. The free base was liberatedby basification and dissolved in ether. Removal of the ether gave1-[1-(2-bromophenyl)cyclobutyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(m.p. 48°-51° C.) which was dried in vacuo (ca 0.1 mmHg) for four hours.

EXAMPLE 69

A mixture of the hydrochloride salt of7-benzyloxy-1-[1-(2-chlorophenyl)cyclobutyl]-6-methoxy-1,2,3,4-tetrahydroisoquinoline(2.75 g prepared in a similar manner to that described in Example RB25),methanol (50 ml) and 37-40% aqueous formaldehyde solution (3 ml) wascooled to 10° C. and sodium cyanoborohydride (1.52 g) was added. Themixture was stirred for 24 hours and the solvents removed byevaporation. The residue was partitioned between ethyl acetate anddilute aqueous sodium hydroxide solution. The organic layer yielded agum which was dissolved in methanol (25 ml) and concentratedhydrochloric acid (25 ml) and heated under reflux for 1 hour. Thesolvents were removed by evaporation and the residue partitioned betweenether and saturated aqueous sodium bicarbonate solution. The ether layeryielded a residue which was dissolved in propan-2-ol (100 ml) and 48%aqueous hydrobromic acid (5 ml). The solvent was removed by evaporationand the residue crystallised and then recrystallised from propan-2-ol togive1-[1-(2-chlorophenyl)cyclobutyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide, m.p. 148°-150° C.

EXAMPLE 70

A mixture of7-benzyloxy-6-methoxy-[1-(2-chlorophenyl)-3,3-dimethylcyclobutyl]-1,2,3,4-tetrahydroisoquinoline(6.1 g, prepared as described in Example RC23), methanol (50 ml) andconcentrated hydrochloric acid (50 ml) was heated under reflux for 20hours. The mixture was cooled and the volume reduced by 25%.7-Hydroxy-6-methoxy-[1-(2-chlorophenyl)-3,3-dimethylcyclobutyl]-1,2,3,4-tetrahydroisoquinoline[m.p. 163°-165° C. (dec)] crystallised and was collected by filtration.

A mixture of7-hydroxy-6-methoxy-[1-(2-chlorophenyl)-3,3-dimethylcyclobutyl]-1,2,3,4-tetrahydroisoquinoline(3.7 g), methanol (50 ml) and 37-40% aqueous formaldehyde solution wascooled to 5° C. Sodium cyanoborohydride (1.4 g) was added and themixture stirred for 1.5 hours. The solvents were removed by evaporationand the residue partitioned between water and dichloromethane. Theorganic layer was washed with aqueous ammonia solution and then brine,dried and the solvent removed by evaporation to give a gum which wasdissolved in propan-2-ol. Addition of 48% aqueous hydrobromic acid gave7-hydroxy-6-methoxy-2-methyl-1-[1-(2-chlorophenyl)-3,3-dimethylcyclobutyl]-1,2,3,4-tetrahydroisoquinolinehydrobromide, m.p. 202°-204° C. (dec).

EXAMPLE 71

Sodium cyanoborohydride (0.8 g) was added to a mixture of7-benzyloxy-6-methoxy-1-[1-(2-methylthiophenyl)cyclobutyl]-3,4-dihydroisoquinoline(2.8 g, prepared as described in Example CA32), acetic acid (20 ml) andmethanol (10 ml) at 0° C. and stirred for 60 hours at ambienttemperature. The mixture was poured onto water (300 ml) and extractedwith dichloromethane. The organic layer was washed with aqueous ammoniasolution (100 ml), then brine (100 ml), and dried over magnesiumsulphate. The solvent was removed by evaporation to yield a gum. The gumwas dissolved in propan-2-ol and treated with excess 48% aqueoushydrobromic acid. Evaporation of the solvent yielded a solid which wastriturated with petroleum ether (b.p. 60°-80° C.), then isolated byfiltration to give7-benzyloxy-6-methoxy-1-[1-(2-methylthiophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline.

A mixture of7-benzyloxy-6-methoxy-1-[1-(2-methylthiophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline.(1.89 g), 37% aqueous formaldehyde solution (3 ml), methanol (30 ml) andsodium cyanoborohydride (0.5 g) was stirred at ambient temperature for24 hours. The mixture was poured onto water (100 ml) and extracted withdichloromethane (300 ml). The extract was washed with dilute aqueousammonia solution to yield a residue which was dissolved in propan-2-oland treated with 48% aqueous hydrobromic acid. The solvent was removedby evaporation to yield7-benzyloxy-6-methoxy-2-methyl-1-[1-(2-methylthiophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinolinewhich was used without further purification.

7-Benzyloxy-6-methoxy-2-methyl-1-[1-(2-methylthiophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline (1.7 g) was heated underreflux for 2 hours with 48% aqueous hydrobromic acid (15 ml) and glacialacetic acid (15 ml). The solvents were removed by evaporation in vacuoand the residue dried by azeotropic distillation with propan-2-ol. Theresidue was then dissolved in propan-2-ol, decolourised with charcoaland the solvent evaporated to yield6,7-dihydroxy-2-methyl-1-[1-(2-methylthiophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline hydrobromide (1.1 g).

EXAMPLE 72

A mixture of7-benzyloxy-6-methoxy-1-[1-(4-trifluoromethoxyphenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline(4.1 g, prepared in a similar manner to that described in Example RC18),37-40% aqueous formaldehyde solution (4.4 ml), acetonitrile (90 ml) andsodium cyanoborohydride (2.32 g) was stirred at 5° C. for 15 minutes,then neutralised with glacial acetic acid and stirred for a further 16hours. The mixture was poured into dilute aqueous sodium hydroxidesolution and extracted with ethyl acetate. The extracts yielded a gumwhich was dissolved in ether and treated with hydrogen chloride to give7-benzyloxy-6-methoxy-2-methyl-1-[1-(4-trifluoromethoxyphenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinolineas the hydrochloride salt.

A mixture of7-benzyloxy-6-methoxy-2-methyl-1-[1-(4-trifluoromethoxyphenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride (2.94 g), industrial methylated spirits (65 ml) andconcentrated hydrochloric acid (65 ml) was heated under reflux for 45minutes. The mixture was concentrated, and dried by azeotropicdistillation with propan-2-ol. The residue was dissolved in ether andtreated with one equivalent of oxalic acid to yield7-hydroxy-6-methoxy-2-methyl-1-[1-(4-trifluoromethoxyphenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinolineoxalate which was crystallised from acetonitrile.

EXAMPLE 73

A mixture of (2-methoxyphenyl)acetonitrile (147 g and 1,2-dibromomethane(168 ml) in dimethylsulphoxide (250 ml) was added over 1 hour to astirred suspension of powdered potassium hydroxide (250 g) and18-Crown-6 (5 g) in dimethylsulphoxide (1200 ml) at 25° C. Stirring wascontinued for 20 hours. Water (1200 ml) was added and the mixtureextracted with ether to give a crude oil which was purified bydistillation (b.p. 102°/0.25) to give 1-(2-methoxyphenyl)cyclopropanecarbonitrile.

1-(2-methoxyphenyl)cyclopropane carbonitrile (24 g) was heated underreflux for 20 hours with 10% aqueous potassium hydroxide solution (150ml). After cooling, the solution was washed with toluene and then ether.The aqueous layer was acidified with excess hydrochloric acid to give1-(2-methoxyphenyl)cyclopropane carboxylic acid.

1-(2-methoxyphenyl)cyclopropane carboxylic acid (19 g) and thionylchloride (30 ml) were heated under gentle reflux for 2 hours. Thesolvent was evaporated to yield 1-(2-methoxyphenyl)cyclopropane carbonylchloride.

A solution of 1-(2-methoxyphenyl)cyclopropane carbonyl chloride (16 g)in ethyl acetate (50 ml) was added to a stirred solution of4-benzyloxy-3-methoxyphenylethylamine hydrochloride (22.3 g) in ethylacetate (250 ml) and triethylamine (30 ml). The mixture was stirred for3 days then water was added. The organic layer was washed with 5M-HCl,then water, then 2M aqueous sodium hydroxide solution, and dried oversodium sulphate. Evaporation yieldedN-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-1-(2-methoxyphenyl)cyclopropanecarboxamide.

A mixture ofN-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-1-(2-methoxyphenyl)cyclopropanecarboxamide (30.3 g) in acetonitrile (450 ml) and phosphoryl chloride(50 ml) was heated under reflux for 80 minutes. The solvent wasevaporated in vacuo below 50° C. and the residue washed with ethylacetate and then stirred with ethyl acetate (300 ml) and ice-cold 5%aqueous ammonia solution (200 ml) for 10 minutes. The organic layer wasdried over potassium carbonate and the solvent removed by evaporation togive7-benzyloxy-6-methoxy-1-[1-(2-methoxyphenyl)cyclopropyl]-3,4-dihydroisoquinoline.

Sodium cyanoborohydride (7.4 g) was added to a stirred mixture of7-benzyloxy-6-methoxy-1-[1-(2-methoxyphenyl)cyclopropyl]-3,4-dihydroisoquinoline (23.3 g) , acetic acid (125 ml) andmethanol (65 ml) cooled by ice/water. After 16 hours at ambienttemperature the mixture was added to sodium hydroxide (110 g) and ice.The product was extracted into ether and the organic layer dried overpotassium carbonate and the solvent removed by evaporation to yield asolid. The solid (16.9 g) in industrial methylated spirits (1800 ml) wasstirred for 3 days with 1M aqueous sodium hydrogen phosphite [340 mlprepared from phosphorous acid (27.9 g) and sodium hydrogen carbonate(28.5 g)] and 37-40% aqueous formaldehyde solution (180 ml). Thesolution was concentrated in vacuo to a volume of 200 ml and basifiedwith potassium carbonate (40 g) in water (200 ml). The mixture wasextracted with ether and the solvent removed from the extract to give agum which was purified by azeotropic distillation with industrialmethylated spirits then propan-2 -ol to yield7-benzyloxy-6-methoxy-1-[1-(2-methoxyphenyl)cyclopropyl]-2-methyl-1,2,3,4-tetrahydroisoquinolinewhich was heated under reflux for 30 minutes with ethanol (200 ml) andconcentrated hydrochloric acid (200 ml). The solvent was removed invacuo to yield a solid which was dried by azeotropic distillation withpropan-2-ol to produce a residue which was dissolved in acetonitrile(200 ml). Ethyl acetate (450 ml) was added, and the mixture boiled. Thesolution was decanted and evaporated in vacuo to give a residue whichwas triturated with cold ethyl acetate. The filtrate deposited furthercrystalline solid which was collected by filtration, washed in ethylacetate and dried. The product yielded was7-hydroxy-6-methoxy-1-[1-(2-methoxyphenyl)cyclopropyl]-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrochloride, m.p. 118° C.

EXAMPLE 74

A mixture of7-benzyloxy-1-[1-(2-chlorophenyl)cyclopropyl]-6-methoxy-1,2,3,4-tetrahydroisoquinolinehydrobromide (5 g prepared as described in Example RC14), methanol (100ml) and 37% aqueous formaldehyde solution (5 ml) was cooled to 10° C.Sodium borohyride (2.5 g) was added and the mixture stirred at ambienttemperature for 2 hours. The methanol was evaporated in vacuo and theresidue partitioned between dilute aqueous sodium hydroxide solution(100 ml) and ether (2×100 ml). The organic layer yielded an oil whichwas dissolved in methanol (25 ml) and concentrated hydrochloric acid (25ml) and heated under reflux for 2 hours. The solvent was removed invacuo and the residue dissolved in hot ethanol, decolorised, filteredand the solvent evaporated. The resulting solid was washed in ether,dried and then partitioned between ethyl acetate and concentratedaqueous ammonia solution. The organic layer yielded an oil which wasdissolved in methanol. 48% Aqueous hydrobromic acid was added and themixture heated under reflux for 2 hours. The solvents were removed byevaporation to yield a solid which was recrystallised from ethanol. Thesolid residue was washed with ether and dried in vacuo at 50° C. to give1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide, m.p. 150°-153° C. Yield 2.95 g.

EXAMPLE 75

A mixture of7-benzyloxy-1-[1-(2-chlorophenyl)cyclopropyl]-6-methoxy-1,2,3,4-tetrahydroisoquinoline(2.1 g, free base liberated from the hydrobromide salt prepared in asimilar manner to that described in Example RC14), acetone (30 ml),anhydrous potassium carbonate (1.6 g) and 2-methoxyethyl bromide (2.1 g)was heated under reflux for 6 hours. After a further 16 hours at ambienttemperature, potassium carbonate (3 g) and 2-methoxyethyl bromide (2.22g) were added, and heating continued for 6 hours. The mixture wasfiltered, the residue washed with acetone, and solvent removed from thefiltrate in vacuo to yield7-benzyloxy-1-[1-(2-chlorophenyl)cyclopropyl]-6-methoxy-2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinolineas an oil.

A mixture of the oil, ethanol (25 ml) and concentrated hydrochloric acid(25 ml) was heated under reflux for 30 minutes. The solvent was removedin vacuo, and the residue dried by azeotropic distillation with ethanol.The resulting residue was triturated with ethyl acetate to give a solidwhich was collected by filtration, washed with ethyl acetate and driedat 40° C. in vacuo to give1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinoline(1.5 g) , m.p. 115°-120° C.

EXAMPLE 76

A mixture of 7 -benzyloxy-1-[1-(2-chlorophenyl)cyclopropyl]-6-methoxy-1,2,3,4-tetrahydroisoquinoline(2.83 g, liberated from the hydrobromide salt prepared in a similarmanner to that described in Example RC14), acetone (40 ml), anhydrouspotassium carbonate (5.5 g) and 2-bromoethanol (3.6 ml) was heated underreflux for 18 hours. The mixture was filtered, the solids washed withacetone, and the filtrate solvent removed in vacuo to give7-benzyloxy-1-[1-(2-chlorophenyl)cyclopropyl]-2-(2-hydroxyethyl)-7-methoxy-1,2,3,4-tetrahydroisoquinolineas an oil.

A mixture of the oil, ethanol (30 ml) and concentrated hydrochloric acid(30 ml) was heated under reflux for 30 minutes. The solvent was removedin vacuo, and the residue dried by azeotropic distillation with amixture of ethanol and toluene. The resulting gum was digested withboiling ethyl acetate and the residue dried at 45° in vacuo to give asolid which was collected by filtration and washed with ethyl acetate.The resulting solid was dissolved in warm water and the resultingsolution basified by addition of a slight excess of aqueous ammoniasolution to yield a solid which was dissolved in ethyl acetate. Theresulting solution was dried over magnesium sulphate and the solventremoved in vacuo to yield a gum which formed a glass on cooling. Theproduct was1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-2-(2-hydroxyethyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline(0.76 g), m.p. 65°-70° C.

EXAMPLE 77

1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinefree base (prepared from the salt described in Example 74) was resolvedby preparative chiral high performance liquid chromatography on aChiracel AD column eluted with a 9:1 mixture of hexane and ethanol. Thesolvent was removed from fraction 1 in vacuo and the residue treatedwith 48% aqueous hydrobromic acid. The water was evaporated in vacuo andthe residue dried by azeotropic distillation with propan-2-ol. Theresulting solid was washed with petroleum ether (b.p. 60°-80° C.),collected by filtration and dried in vacuo to yield(+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide which had a specific optical rotation α_(D) of +14.6, m.p.154°-157° C.

EXAMPLE 78

A mixture of6,7-dimethoxy-1-[1-(4-biphenylyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride (3.5 g, prepared as described in Example RC20), methanol(50 ml), 37% aqueous formaldehyde solution (5 ml) and sodiumcyanoborohydride (2.08 g) was stirred at ambient temperature for 24hours. The solvents were removed in vacuo and the residue waspartitioned between aqueous sodium hydroxide solution and ether. Theether extracts were dried over magnesium sulphate, the solution wasfiltered and the solvent removed in vacuo. The residue was dissolved inglacial acetic acid (30 ml). 48% Aqueous hydrobromic acid (30 ml) wasadded, and the mixture was heated under reflux under nitrogen for 6hours. The solvents were removed in vacuo and the residue wasrecrystallised from methanol to give a solid which was partitionedbetween concentrated aqueous ammonia solution and ether. The etherextracts were washed with brine, dried and filtered. Dry hydrogenchloride was bubbled through the filtrate to yield6,7-dihydroxy-2-methyl-1-[1-(4-biphenylyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride (1.1 g), m.p. 131°-135° C. (dec).

EXAMPLE 79

1-[1-(2-Chlorophenyl)cyclopropyl]carbonyl chloride (16.9 g) was addeddropwise at 0° C. under nitrogen to a suspension of2-(4-methoxy-3-methylphenyl)ethylamine (13 g, prepared in a similarmanner to that described in Example 10) and triethylamine (11.8 ml) intetrahydrofuran (200 ml). The reaction mixture was stirred at ambienttemperature for 16 hours, then poured onto aqueous sodium hydroxidesolution and stirred for 1 hour. The product was extracted witch ethylacetate. The extracts were dried over magnesium sulphate and the solventwas concentrated to giveN-[2-(4-methoxy-3-methylphenyl)ethyl]-1-(2-chlorophenyl)cyclopropane-carboxamidewhich was used without further purification.

A mixture of the amide and 82% w/w solution of polyphosphate ester inchloroform (170 g) was heated gently for 16 hours, then poured intowater (1200 ml) and the mixture washed with ether. The aqueous phase wasbasified by addition of aqueous ammonia solution and the product wasextracted with ethyl acetate. The extracts were dried and concentratedto give1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-6-methyl-3,4-dihydroisoquinolineas a solid. Yield 14.7 g.

Sodium cyanoborohydride (5.3 g) was added portionwise to a solution of1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-6-methyl-3,4-dihydroisoquinoline(14 g) in methanol (70 ml) and acetic acid (140 ml). The mixture wasstirred for 1 hour, concentrated, and the residue then treated withaqueous sodium hydroxide solution. The resulting mixture was extractedwith ethyl acetate and the extracts were washed with brine and driedover magnesium sulphate.1-[1-(2-Chlorophenyl)cyclopropyl]-7-methoxy-6-methyl-1,2,3,4-tetrahydroisoquinolinecrystallised from the extract and was collected by filtration (6.5 g).

A mixture of1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-6-methyl-1,2,3,4-tetrahydroisoquinoline(6.2 g), methanol (160 ml) and 37-40% aqueous formaldehyde solution wasstirred for 15 minutes. Sodium cyanoborohydride (5.13 g) was added andthe mixture was stirred for a further 10 minutes. The reaction was thenneutralised with acetic acid and stirred for 45 minutes. The methanolwas removed in vacuo and the residue treated with aqueous sodiumhydroxide solution. The product was extracted with ethyl acetate. Theextracts were washed with aqueous ammonia solution, water and brine,then dried over magnesium sulphate. Concentration yielded1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-2,6-dimethyl-1,2,3,4-tetrahydroisoquinolineas a gum (5.02 g).

A mixture of the gum (5.02 g), 48% aqueous hydrobromic acid (120 ml) andglacial acetic acid (120 ml) was heated at 90°-95° C. for 16 hours. Thereaction was neutralised by addition of aqueous sodium hydroxidesolution and the product extracted with ethyl acetate. The extracts wereconcentrated and the residue redissolved in propan-2-ol (150 ml)containing concentrated aqueous hydrochloric acid (2 ml). The solutionwas concentrated and dried by azeotropic distillation with propan-2-olto give a solid. The solid was washed with ethyl acetate and dried togive1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-2,6-dimethyl-1,2,3,4-tetrahydroisoquinolinehydrochloride. Yield 4.5 g, m.p. 159°-161° C. (dec).

EXAMPLE 80

1-[1-(2-Chlorophenyl)cyclopropyl]-7-hydroxy-2,6-dimethyl-1,2,3,4-tetrahydroisoquinoline(2.0 g liberated from the salt prepared as described in Example 79) wasresolved by chiral preparative high performance liquid chromatography ona Chiracel OD column eluted with a 1:19 mixture of propan-2-ol andhexane. Fraction 1 was converted into its hydrobromide salt using 48%aqueous hydrobromic acid in propan-2-ol to yield (+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-2,6-dimethyl-1,2,3,4-tetrahydroisoquinolinehydrobromide. The salt had a specific optical rotation α_(D) of +5.6°,m.p. 170°-175° C. (dec). Yield 0.8 g.

EXAMPLE 81

Sodium cyanoborohydride (2.8 g) was added at 5° C. to a mixture of1-[1-(2,4-dichlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-1,2,3,4-tetrahydroisoquinolinehydrobromide (10 g, prepared as described in Example RC4), methanol (100ml) and 37-40% aqueous formaldehyde solution (7.2 ml). The mixture waswarmed to ambient temperature and stirred for 1.5 hours. The solvent wasremoved in vacuo and the residue partitioned between water anddichloromethane. The organic phase was washed with concentrated ammoniasolution, then water, and dried over magnesium sulphate. The solvent wasremoved in vacuo to yield1-[1-(2,4-dichlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolineas a gum which solidified on standing.

A mixture of 1 -[1-(2,4-dichlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(8.5 g), 48% aqueous hydrobromic acid (100 ml) and glacial acetic acid(100 ml) was heated under reflux for 2 hours. The solvents were removedin vacuo and the residue dried by azeotropic distillation withpropan-2-ol. The resulting solid was recrystallised from propan-2-ol toyield1-[1-(2,4-dichlorophenyl)cyclopropyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide (7.2 g), m.p. 235°-237° C.

EXAMPLE 82

N,N,N',N'-Tetramethylethylenediamine (231.4 g) was added at ambienttemperature to a solution of n-butyl lithium (2.5M, 800 ml) in hexane(2.5 l) followed by a solution of 2,3-dihydrobenzo[b]furan (102 g) inhexane (25 ml). The mixture was stirred under nitrogen at ambienttemperature for 5 hours. The resulting suspension was added slowly todry ice (300 g) and hexane (500 ml) under nitrogen. After stirring atambient temperature for 16 hours, the mixture was diluted with water (2l), and the layers separated. The aqueous layer was washed with hexane,acidified to pH 1 with concentrated hydrochloric acid, cooled and theprecipitate collected by filtration. This was washed with water anddichloromethane and dried at 80° C. in vacuo to give2,3-dihydrobenzo[b]furan-7-carboxylic acid (39.6 g), m.p. 164°-165° C.The hexane layer was filtered, dried over sodium sulphate andconcentrated. On cooling, further product was obtained (32.7 g), m.p.170° C.

Borane dimethyl-sulphide complex (60 ml) was added to a stirred solutionof the above acid (70.2 g) and tetrahydrofuran (500 ml). The mixture wasstirred for 30 minutes, then water (200 ml) was carefully added. Thetetrahydrofuran was removed in vacuo. Water (200 ml) and then aqueoussodium hydroxide solution were added. The product was extracted intoether, and the extracts dried over potassium carbonate. The solvent wasremoved in vacuo to yield 7-hydroxymethyl-2,3-dihydrobenzo[b]furan (50g) as an oil.

A solution of the above oil (50 g) in dichloromethane (200 ml) wastreated portionwise at 20° C. with thionyl chloride (50 ml) over 10minutes. The solution was warmed, and the solvent removed in vacuo togive 7-chloromethyl-2,3-dihydrobenzo[b]furan as an oil which was usedwithout further purification.

A solution of sodium cyanide (45 g) in water (200 ml) was added to amixture of the above oil in toluene (200 ml). Tetrabutylammonium bromide(2 g) was added. The mixture was heated under reflux with vigorousstirring for 3 hours. After standing for 16 hours, the mixture wasdecolourised by addition of charcoal. The mixture was filtered,separated, and the organic layer dried over sodium sulphate. The solventwas removed in vacuo to give an oil (40 g) which was purified bydistillation at 144-160° C./4 mbar and then at 90°-112° C./0.4 mbar. Thedistillate was heated with dimethylsulphoxide (50 ml) and sodium cyanide(6 g) at 90°-95° C. for 8 hours with the exclusion of moisture. Themixture was then added to water and the product was extracted intoether. The extracts were dried over potassium carbonate and the solventwas removed in vacuo to yield an oil.

A mixture of the oil, toluene (60 ml), pyridine (2.2 ml) and phthalicanhydride (4 g) was heated at 90°-95° C. for 4 hours. The resultingsolution was cooled, washed with 10% aqueous potassium carbonatesolution, then with dilute hydrochloric acid. The solution was thendried over sodium sulphate and the solvent removed in vacuo to yield anoil. The oil was distilled, (b.p. 120° C./1 mbar) to give2,3-dihydrobenzo[b]furan-7-ylacetonitrile which rapidly solidified(16.97 g).

The solid (16.97 g) was melted and dissolved in dimethylsulphoxide (100ml). 1,2-Dibromoethane (18 ml) was added and the mixture was added at 1drop/second at 20°-30° C. to a stirred mixture of solid potassiumhydroxide (50 g), dimethylsulphoxide (150 ml) and 18-Crown-6 (1.5 g).The mixture was stirred for a further 16 hours. 1,2-Dibromoethane (10ml) was added and the stirring continued for 8 hours. The mixture wasallowed to stand at ambient temperature for 16 hours. 1,2-Dibromoethane(8 ml) was added, the mixture was stirred for 6 hours, then further1,2-dibromoethane (10 ml) was added and the mixture stood for 3 days.The mixture was added to water and the product extracted with ether. Theextracts were dried over potassium carbonate, the solvent removed invacuo, and the residue distilled (b.p. 120° C./0.25 mbar) to yield1-[2,3-dihydrobenzo[b]-furan-7-yl]cyclopropane carbonitrile as a solid(11.2 g).

A mixture of the above solid (11.2 g), potassium hydroxide (30 g) andwater (300 ml) was stirred and heated under reflux for 6 hours. Theresulting solution was washed with ether and the aqueous phase acidifiedby addition of excess hydrochloric acid, to give a solid which wascollected by filtration, washed with water and dried in air to yield1-[2,3-dihydrobenzo[b]furan-7-yl]cyclopropane carboxylic acid.

The above carboxylic acid (7.7 g) was warmed with thionyl chloride (20ml) then heated under reflux for 20 minutes. Excess thionyl chloride wasboiled off. Distillation yielded an oil (b.p. 70° C./50 mbar) which wasdissolved in ethyl acetate (50 ml). The solution was added to a stirredmixture of 2-(4-benzyloxy-3-methoxyphenyl)ethylamine hydrochloride (15.7g), ethyl acetate (200 ml) and triethylamine (30 ml) and the mixturestirred for 64 hours. Water was added. The ethyl acetate layer waswashed with water, dilute aqueous sodium hydroxide solution, dilutehydrochloric acid and water, then dried over sodium sulphate. Thesolvent was removed in vacuo to give a gum which was purified by flashchromatography using ether as the eluant to giveN-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-1-[2,3-dihydrobenzo[b]furan-7-yl]cyclopropanecarboxamide which was dissolved in acetonitrile (200 ml). Phosphorylchloride (20 ml) was added and the mixture heated under reflux for 80minutes. The solvent and excess phosphoryl chloride were removed invacuo and the residue was dissolved in ethyl acetate. Ether was addedcausing an oil to separate. The supernatant liquid was decanted andether was added until no further oil separated. The oil was trituratedwith ether, then added to a mixture of dilute aqueous ammonia and ether.The ether layer was dried over potassium carbonate and the solventremoved in vacuo to give7-benzyloxy-1-[1-(2,3-dihydrobenzo[b]furan-7-yl)cyclopropyl]-6-methoxy-3,4-dihydroisoquinolineas a gum (11.1 g).

A mixture of the above gum (11.1 g), acetic acid (60 ml) and methanol(30 ml) was stirred for 2 hours, then cooled in ice/water. Sodiumcyanoborohydride in tetrahydrofuran (1M solution, 53 ml) was added andthe mixture stirred for 2 hours. Water, then excess aqueous ammoniasolution were added and the product was extracted with ether. Thesolvent was removed in vacuo to yield a gum which was used withoutfurther purification.

1M aqueous sodium hydrogen phosphite [218 ml, prepared from phosphorousacid (17.9 g) in water and sodium bicarbonate (18.3 g)] was added to amixture of the gum and industrial methylated spirits (1.15 1). 37-40%Aqueous formaldehyde solution (115 ml) was added and the resultingsolution was allowed to stand for 64 hours. The solution wasconcentrated in vacuo to 200 ml, filtered and decanted to remove tracesof gum. The solution was diluted with water, basified by addition ofexcess aqueous ammonia solution, and the product was extracted intoether. The extracts were dried over sodium sulphate and the solventremoved in vacuo to yield an oil. The oil was purified by columnchromatography using a 19:1 mixture of ether and triethylamine aseluant. The fractions were purified by high pressure liquidchromatography. Fractions 1 and 2 (9.46 g) were combined.

A mixture of fractions 1 and 2 (9.46 g), 98-100% formic acid (25 ml) andmethanol (125 ml) under argon was treated with 10% palladium on charcoal(3 g) was added and argon bubbled through for 24 hours. 48% Aqueoushydrobromic acid (3.6 ml) was added and the mixture was filtered and thesolvent removed from the filtrate in vacuo. The residue was dried byazeotropic distillation with ethanol (100%) to give a solid which waswashed with ethyl acetate, dried in air and then in vacuo at 45° C.

The solid was dissolved in water, basified by addition of aqueousammonia solution and extracted with ethyl acetate. The extract was driedover sodium sulphate and the solvent removed in vacuo to leave a smallvolume. Ether was added and1-[1-(2,3-dihydrobenzo[b]furan-7-yl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(5.18 g), m.p. 156° C. was collected by filtration and washed withether.

EXAMPLE 83

A mixture of N-[2-(3,4-dimethoxyphenyl)ethyl]cyclobutanecarboxamide (44g, prepared in a similar manner to that described in Example E46),phosphorus oxychloride (150 ml) and acetonitrile (900 ml) was heatedunder reflux for 2.5 hours. The cooled solution was poured onto diluteaqueous ammonia solution and the product was extracted into ethylacetate. The extracts were washed with brine, dried and the solventremoved in vacuo. The resulting oil solidified on standing for 16 hours.The solid was recrystallised from petroleum ether (b.p. 60°-80° C.) togive 1-cyclobutyl-3,4-dihydro-6,7-dimethoxyisoquinoline (20 g).

n-Butyl lithium (24.5 ml, 2M solution in hexane) was added to a solutionof diisopropylamine (6.85 ml) in tetrahydrofuran (50 ml) at 0° C. Theresulting solution of lithium diisopropylamide was stirred at 0° C. for20 minutes. A solution of1-cyclobutyl-3,4-dihydro-6,7-dimethoxyisoquinoline (10 g) intetrahydrofuran (100 ml) was added. The mixture was stirred at 0° C. for1 hour, then cooled to -70° C. and treated dropwise with2-fluorobenzonitrile (4.42 ml). The mixture was stirred at -70° C. for50 minutes, then allowed to warm slowly to ambient temperature. Themixture was poured onto hydrochloric acid and washed with ether. Theaqueous phase was basified with ammonia solution and the product wasextracted with ethyl acetate. The resulting solid (0.6 g) was collectedby filtration. The filtrate was washed with brine, dried over magnesiumsulphate and the solvent removed in vacuo to give further solid. Thecombined solids were recrystallised from acetonitrile yielding a solidwhich was dried in vacuo to give1-[1-(2-cyanophenyl)cyclobutyl]-6,7-dimethoxy-3,4-dihydroisoquinoline (5g).

A mixture of the dihydroisoquinoline (5 g), acetonitrile (150 ml) andmethyl iodide (18 ml) was heated under gentle reflux for 64 hours. Thesolvent was removed in vacuo and the residue was washed with ether. Thesolid was collected by filtration and dried in vacuo to yield1-[1-(2-cyanophenyl)cyclobutyl]-6,7-dimethoxy-2-methyl-3,4-dihydroisoquinoliniumiodide (6.7 g).

Sodium borohydride (0.465 G) was added portionwise to a mixture of1-[1-(2-cyanophenyl)cyclobutyl]-6,7-dimethoxy-2-methyl-3,4-dihydroisoquinoliniumiodide (6 g) and methanol (40 ml). The mixture was stirred for 2 hoursthen poured onto aqueous sodium hydroxide solution and the productextracted into ether. The solvent was removed from the extracts to givea gum which was dissolved in ethyl acetate and a little propan-2-ol. A0.4M solution of (±)-dibenzoyltartaric acid in ether (35 ml) was addedand the resulting suspension was concentrated in vacuo. The residualsolid was washed with ether to give1-[1-(2-cyanophenyl)cyclobutyl]-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(±)-dibenzoyltartrate (7.2 g), m.p. 109°-112° C. (dec).

The (±)-dibenzoyltartrate salt (2 g) was neutralised with aqueoussaturated sodium hydrogen carbonate solution and extracted with ethylacetate. The extracts were dried and the solvents removed to give1-[1-(2-cyanophenyl)cyclo-butyl]-6,7-dimethoxy-2-methyl-1,2,3,4,-tetrahydroisoquinolinefree base (1 g) which was dissolved in dichloromethane (5 ml). Thesolution was cooled to -70° C. and treated dropwise with a 1M solutionof boron tribromide in dichloromethane (3 ml). After 30 minutes themixture was allowed to warm to ambient temperature, and then stirred for90 minutes. The mixture was cooled to -70 ° C. and furtherdichloromethane (7 ml ) and a solution of 1M boron tribromide indichloromethane (3 ml ) were added. The mixture was warmed to roomtemperature and stirred for 1 hour then cooled to -40° C. and an excessof methanol was added. The mixture was warmed to ambient temperature andmethanol (100 ml) was added. The solvents were distilled off in vacuoand the trimethylborate removed by azeotropic distillation withmethanol.

The residue was neutralised with aqueous saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The extracts weretreated with excess ethereal hydrogen chloride. The solvent was removedin vacuo to yield 1-[1-(2-cyanophenyl)cyclobutyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.4 g), m.p.206°-208° C. (dec).

EXAMPLE 84

Methyl iodide (15 ml) was added to a solution of7-benzyloxy-1-[1-(2-chlorophenyl)cyclopentyl]-6-methoxy-3,4-dihydroisoquinoline(13 g, prepared as described in Example CA34) in acetonitrile (100 ml).The mixture was heated under reflux for 24 hours, cooled and theresulting solid collected by filtration. The solid was washed with etherand dried in air to give7-benzyloxy-1-[1-(2-chlorophenyl)cyclopentyl]-6-methoxy-2-methyl-3,4-dihydroisoquinoliniumiodide (10 g).

Sodium borohydride (2.6 g) was added portionwise to a mixture of7-benzyloxy-1-[1-(2-chlorophenyl)cyclopentyl]-6-methoxy-2-methyl-3,4-dihydroisoquinoliniumiodide (10 g) and methanol (250 ml). The mixture was stirred at ambienttemperature for 1 hour, heated under reflux for 1 hour, then cooled toambient temperature. Sodium borohydride (5 g) was added and the mixturestirred at ambient temperature for 30 minutes. The resulting solid wascollected by filtration, washed with ether and dissolved in acetone.Insoluble particles were removed by filtration and the solvent wasremoved from the filtrate in vacuo to yield7-benzyloxy-1-[1-(2-chlorophenyl)cyclopentane]-6-methoxy-2-methyl-1,2,3,4tetrahydroisoquinoline(3.8 g).

A mixture of the above tetrahydroisoquinoline (3.8 g), methanol (25 ml)and concentrated hydrochloric acid (25 ml) was heated under reflux for3.5 hours. The solvents were removed in vacuo and the residuerecrystallised from methanol. The resulting solid was washed twice withether and dried to yield1-[1-(2-chlorophenyl)cyclopentyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.8 g), m.p. 119°-121° C.(dec).

EXAMPLE 85

A solution of7-benzyloxy-1-[1-(2-chlorophenyl)cyclopropyl]-6-methoxy-3,4-dihydroisoquinoline(0.5 g, prepared in a similar manner to that described in Example CA281)in dichloromethane (10 ml) was added dropwise at -40° C. to a stirredsolution of sodiumtris[N-(2-methylpropyloxycarbonyl)prolyloxy]borohydride (2.43 g) indichloromethane (10 ml). The mixture was allowed to reach ambienttemperature and was stirred for 49 hours. Dilute sulphuric acid (10 ml,10% v/v) was added, and stirring continued for 1 hour. The mixture wasbasified by addition of saturated aqueous sodium carbonate solution. Theorganic layer was washed with brine, dried over magnesium sulphate andthe solvent removed in vacuo to yield7-benzyloxy-1-[1-(2-chlorophenyl)cyclopropyl]-6-methoxy-1,2,3,4-tetrahydroisoquinolineas a gum (0.42 g). This product was shown to have a 92% enantiomericexcess of one of the enantiomers.

A mixture of the enantiomerically enriched7-benzyloxy-1-[1-(2-chlorophenyl)cyclopropyl]-6-methoxy-1,2,3,4-tetrahydroisoquinoline(0.41 g), anhydrous potassium carbonate (0.4 g), methyl iodide (0.152 g)and acetone (25 ml) was stirred at ambient temperature for 2 hours. Thesolvent was removed in vacuo and the residue dissolved in water andextracted with ether. The extracts were concentrated in vacuo. A mixtureof the residue, concentrated hydrochloric acid (5 ml) and methanol (5ml) was heated under reflux for 2 hours. The solvents were removed invacuo and the residue partitioned between saturated aqueous sodiumbicarbonate solution and ether. The ether layer was concentrated invacuo and the residue dissolved in propan-2-ol and acidified with 48%aqueous hydrobromic acid. The solution was concentrated in vacuo toyield(+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide (0.24 g).

EXAMPLE 86

Decanoyl chloride (0.45 g) was added to a mixture of(+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide (1 g, prepared in a similar manner to that described inExample 77), triethylamine (0.7 g) and ether (30 ml). The mixture wasstirred at ambient temperature for 24 hours, then washed with water, 10%aqueous sodium hydroxide solution, and brine. The organic layer wasdried over magnesium sulphate, filtered and concentrated to yield a gumwhich was purified by chromatography on a silica gel column using a 1:3mixture of ether and light petroleum as eluant. The relevant fractionswere concentrated in vacuo to yield(+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-decanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(0.95 g) as a gum; having specific optical rotation α_(D) of +21.47°.

EXAMPLE 87

Decanoyl chloride (0.66 g) in dichloromethane (5 ml) was added to astirring mixture of(+)-1-[1-(2-chlorophenyl)cyclobutyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide (1.5 g, prepared in a similar manner to that described inExample 64), triethylamine (1.06 g) and dichloromethane (25 ml). Themixture was stirred at ambient temperature for 20 minutes, then water(20 ml) was added and stirring continued for 1 hour. The organic layerwas washed with saturated aqueous sodium bicarbonate solution, water andbrine, then dried over magnesium sulphate, filtered and concentrated invacuo to yield(-)-1-[1-(2-chlorophenyl)cyclobutyl]-7-decanoyloxy-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline(1.31 g). This had a specific optical rotation α_(D) of -5.59°.

EXAMPLE 88

Decanoyl chloride (0.61 g) was added to a stirring suspension of (+)-1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide (1 g, prepared in a similar manner to that described inExample 62) and dichloromethane (25 ml). Triethylamine (1.35 ml) wasadded and the stirring was maintained for 1.5 hours. Water was thenadded, and the organic layer washed with 2N aqueous sodium hydroxidesolution, then water and dried over potassium carbonate. The solvent wasremoved in vacuo and the residual oil was purified by liquidchromatography using petroleum ether (b.p. 40°-60° C.) as impurityeluant, then 5% ether in petroleum ether (b.p. 40°-60° C.) as producteluant. The solvent was removed in vacuo to yield(+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-decanoyloxy-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline(0.85 g) which had a specific optical rotation α_(D) of +10.6°.

EXAMPLE 89

Decanoyl chloride (0.5 g) in dichloromethane, then triethylamine (0.8 g)was added to a stirring mixture of1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrobromide (0.825 g, prepared in a similar manner to that described inExample 61) in dichloromethane (20 ml). After stirring for 1 hour, waterwas added, and the organic phase was washed with 2N aqueous sodiumhydroxide solution then water. The organic phase was then dried overmagnesium sulphate and the solvent removed in vacuo to yield1-[1-(2-chlorophenyl)cyclopropyl]-7-decanoyl-oxy-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline(0.85 g).

EXAMPLE 90

Hexadecanoyl chloride (0.83 g) in dichloromethane (5 ml) was addeddropwise to a stirring solution of1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(1.04 g, prepared from the (+)-enantiomer of the hydrobromide salt,prepared in a similar manner to that described in Example 77),triethylamine (0.91 g) and dichloromethane (20 ml). The mixture wasstirred at ambient temperature for 2 hours, then washed with dilutesodium hydroxide solution, water and brine. The organic phase was driedover magnesium sulphate, filtered and concentrated in vacuo. Theresulting oil was dissolved in petroleum ether (b.p. 60°-80° C.) andwashed repeatedly with water. The organic layer was dried over magnesiumsulphate, filtered and concentrated in vacuo to yield(+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-hexadecanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinoline(1.45 g) which had a specific optical rotation α_(D) of +21.18°.

EXAMPLE 91

A solution of dodecanoyl chloride (0.737 g) in dichloromethane (5 ml)was added dropwise to a stirred solution of1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(1.16 g, free base liberated from the (+)-enantiomer of the hydrobromidesalt prepared as described in Example 77), triethylamine (1.02 g) anddichloromethane (20 ml). The mixture was stirred at ambient temperaturefor 2 hours. The mixture was washed with dilute sodium hydroxidesolution, water then brine. The organic layer was concentrated in vacuoand the residue partitioned between light petroleum ether and water.

The organic layer was washed with water, dried over magnesium sulphate,filtered and the solvent removed in vacuo to yield a gum. The gum wasdissolved in petroleum ether and purified by flash chromatography usinga 1:4 mixture of ether and petroleum ether as eluant. Removal of solventfrom the eluate yielded(+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-dodecanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(0.81 g) which had a specific optical rotation α_(D) of +25.05°.

EXAMPLE 92

A solution of heptanoyl chloride (0.34 g) in dichloromethane (5 ml) wasadded dropwise to a stirred solution of1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(0.79 g, free base liberated from the (+)-enantiomer of the hydrobromidesalt, prepared as described in Example 77), triethylamine (0.69 g) anddichloromethane (20 ml). The mixture was stirred at ambient temperaturefor 2 hours. The mixture was washed with dilute sodium hydroxidesolution, water then brine. The organic layer was concentrated in vacuoand the residue partitioned between light petroleum ether and water.

The organic layer was washed with water, dried over magnesium sulphate,filtered and the solvent removed in vacuo to yield a gum. The gum wasdissolved in petroleum ether and purified by flash chromatography usinga 1:3 mixture of ether and petroleum ether as eluant. Removal of solventfrom the eluate yielded(+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-heptanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.64 g) which had aspecific optical rotation α_(D) of +23.04°.

EXAMPLE 93

A solution of octadecanoyl chloride (0.61 g) in dichloromethane (5 ml)was added dropwise to a stirred solution of 1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(0.69 g, free base liberated from the (+)-enantiomer of the hydrobromidesalt prepared as described in Example 77), triethylamine (0.61 g) anddichloromethane (20 ml). The mixture was stirred at ambient temperaturefor 2 hours. The mixture was washed with dilute sodium hydroxidesolution, water then brine. The organic layer was concentrated in vacuoand the residue partitioned between light petroleum ether and water.

The organic layer was washed with water, dried over magnesium sulphate,filtered and the solvent removed in vacuo to yield a gum. The gum wasdissolved in petroleum ether and purified by flash chromatography usinga 1:3 mixture of ether and petroleum ether as eluant. This yielded(+)-1-[1-(2-chlorophenyl)cyclopropyl]-6-methoxy-2-methyl-7-octadecanoyloxy-1,2,3,4-tetrahydroisoquinoline(0.41 g) which had a specific optical rotation α_(D) of +23.33°.

EXAMPLES MI ##STR28##

A mixture of a compound of formula VI in which OR₃, R₄ and G are asdefined in Table MI and E is --(CH₂)₃ -- (a g), methyl iodide (b g),anhydrous potassium carbonate (c g) and acetone (d ml) was stirred atambient temperature for e hours. The mixture was filtered and thesolvent removed by evaporation. The residue was partitioned betweenethyl acetate and water. The ethyl acetate layer yielded a residue whichwas treated as set out in the Notes below to give the desired compoundof formula IV in which OR₃, R₄ and G are as defined in Table MI, R₂ ismethyl and E is --(CH₂)₃ --.

NOTES TO TABLE MI

ND indicates that the melting point was not determined.

MI1 The final residue was triturated with a 5:1 mixture of lightpetroleum ether (b.p. 60°-80° C.) and ether. The product wascharacterised by recrystallising a small sample from light petroleumether. It is the melting point of this recrystallised sample which isgiven in Table MI.

MI2 The residue from the initial reaction was partitioned between etherand water. Evaporation of the ether layer yielded the product which wascharacterised by recrystallising a small sample from light petroleumether. It is the melting point of this recrystallised sample which isgiven in Table MI.

MI3 The product was characterised by converting a small sample into itshydrochloride salt. The melting point of this salt is given in the lastcolumn of Table MI.

MI4 The product was characterised by recrystallising a small sample frompetroleum ether (bp 60°-80° C.). It is the melting point of thisrecrystallised sample which is given in Table MI.

MI5 The product was characterised by converting a small sample into itsoxalate salt, the melting point of this salt is given in the last columnof Table MI.

MI6 The residue from the initial reaction was partitioned between etherand aqueous ammonia solution. Evaporation of the ether layer yielded asolid which was dissolved in propan-2-ol (50 ml) and 48% aqueoushydrobromic acid solution (20 ml). Evaporation yielded a residue whichwas dried by azeotropic distillation with propan-2-ol, then dissolved inmethanol, treated with charcoal and the resulting solid was trituratedwith propan-2-ol and crystallised from ether. The product in the form ofa hydrobromide salt was used without further purification.

                                      TABLE MI                                    __________________________________________________________________________    Ex OR.sub.3                                                                          R.sub.4                                                                           G       SM  a  b c d  e Note                                                                             mp                                      __________________________________________________________________________    MI1                                                                              7-OMe                                                                             6-F 4-chlorophenyl                                                                        RC1 5.8                                                                              2.6                                                                             4.6                                                                             50 2 MI1                                                                              96-97                                   MI2                                                                              7-OMe                                                                             6-F 4-bromophenyl                                                                         RC2 4.2                                                                              1.9                                                                             3 100                                                                              1 MI2                                                                              97-98                                   MI3                                                                              7-OMe                                                                             6-OMe                                                                             3-trifluoro-                                                                          RB6 11 4 7.1                                                                             100                                                                              16                                                                              MI3                                                                              156-158                                            methylphenyl                                                       MI4                                                                              7-OMe                                                                             6-F 2,4-dichloro-                                                                         RC3 3  1.2                                                                             2.2                                                                             50 2 MI4                                                                              125-127                                            phenyl                                                             MI5                                                                              8-OMe                                                                             5-Cl                                                                              phenyl  RB22                                                                              10.5                                                                             5 8.9                                                                             100                                                                              1 MI5                                                                              132-135                                 MI6                                                                              7-OMe                                                                             6-Ph                                                                              2-chlorophenyl                                                                        RC22                                                                              7.5                                                                              2.3                                                                             5.1                                                                             215                                                                              4 MI6                                                                              ND                                      __________________________________________________________________________

EXAMPLES MF ##STR29##

A mixture of a compound of formula VI in which OR₃, R₄ and G are asidentified in Table MF and E is --(CH₂)₃ -- (a g), 37-40% aqueousformaldehyde solution (b ml), sodium cyanoborohydride (c g) andacetonitrile (d ml) was stirred for 15 minutes. Glacial acetic acid wasadded to neutralise the solution and stirring was continued for afurther 45 minutes. The mixture was concentrated by evaporation andbasified with 2N aqueous potassium hydroxide solution. The resultingmixture was extracted with ether and the ether extracts washed withaqueous potassium hydroxide solution. The product was extracted intoaqueous hydrochloric acid. The acid extract was basified and extractedwith ether. The ether extract yielded a residue which was a compound offormula IV in which OR₃, R₄ and G are as identified in Table MF, E is--(CH₂)₃ -- and R₂ is methyl.

NOTES TO TABLE MF

MF1 The residue was used without further treatment. Its melting point isgiven in the last column of Table MF.

MF2 The residue was characterised by converting a small sample into itshydrochloride salt. The melting point of this hydrochloride salt isgiven in the last column of Table MF.

MF3 The residue was converted into its hydrochloride salt which wasrecrystallised from propan-2-ol. The melting point of this salt is givenin the last column of Table MF.

MF4 The product of Example RB5 was converted to its free base which wasused as the starting material. The product in the form of its free basewas obtained as a gum. The nmr spectrum was consistent with the requiredstructure.

                                      TABLE MF                                    __________________________________________________________________________    Ex OR.sub.3                                                                          R.sub.4                                                                           G       SM a  b  c  d  Note                                                                             mp                                       __________________________________________________________________________    MF1                                                                              7-OMe                                                                             6-OMe                                                                             2-bromophenyl                                                                         RB1                                                                              3  2.9                                                                              0.74                                                                             90 MF1                                                                              92-93                                    MF2                                                                              7-OMe                                                                             6-OMe                                                                             2-chlorophenyl                                                                        RB2                                                                              7.2                                                                              7.92                                                                             2  160                                                                              MF1                                                                              94-96                                    MF3                                                                              7-OMe                                                                             6-OMe                                                                             4-fluorophenyl                                                                        RB3                                                                              7  8.2                                                                              2.1                                                                              165                                                                              MF2                                                                              189-190                                                                       (dec)                                    MF4                                                                              7-OMe                                                                             6-OMe                                                                             2-methylphenyl                                                                        RB4                                                                              8.3                                                                              9.4                                                                              2.4                                                                              190                                                                              MF3                                                                              195                                                                           (dec)                                    MF5                                                                              7-OMe                                                                             6-OMe                                                                             2-fluorophenyl                                                                        RB5                                                                              13.7                                                                             16 3  320                                                                              MF4                                         __________________________________________________________________________

EXAMPLE MF6

A mixture of the oxalate salt of1-[1-(2-chlorophenyl)cyclobutyl]-7-methoxy-6-methyl-1,2,3,4-tetrahydroisoquinoline(4.42 g prepared as described in Example RC12), methanol (87 ml) and37-40% aqueous formaldehyde solution (5.1 ml) was cooled to 10° C. andsodium cyanoborohydride (2.64 g) was added. After 10 minutes the mixturewas allowed to warm to ambient temperature and was stirred for 24 hours.The reaction mixture was concentrated and the residue partitionedbetween ethyl acetate and dilute aqueous sodium hydroxide solution. Theorganic phase was washed with aqueous ammonia solution, then dried andconcentrated to yield1-[1-(2-chlorophenyl)cyclobutyl]-7-methoxy-2,6-dimethyl-1,2,3,4-tetrahydroisoquinoline(3.3 g).

EXAMPLE MF7

A mixture of1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline(2.5 g, prepared as described in Example RC10), 37-40% aqueousformaldehyde solution (2.9 ml), sodium cyanoborohydride (0.75 g) andacetonitrile (100 ml) was stirred for 15 minutes. Glacial acetic acidwas added to neutralise the solution and stirring was continued for afurther 45 minutes. The mixture was basified with aqueous sodiumhydroxide solution, then extracted with ethyl acetate. The extractsyielded1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

EXAMPLES RB ##STR30##

A compound of formula VII in which OR₅ is the group OR₃ as identified inTable RB and R₄, E and G are as identified in Table RB (a g) in methanol(b ml) was treated with sodium borohydride (c g) added portionwise withstirring. When thin layer chromatography showed that the reduction wassubstantially complete, the reaction mixture was concentrated, water wasadded and the resulting mixture extracted with the solvent shown incolumn d (a=ethyl acetate, b=ether or c=dichloromethane). The extractswere dried and the solvent removed by evaporation to give a residuewhich was treated as shown by the Notes to Table RB to give a compoundof formula VI in which OR₃, R₄, E and G are as identified in Table RB.

NOTES TO TABLE RB

The abbreviation "OBz" represents benzyloxy. In column E of Table RB, Wrepresents --CH₂.CMe₂.CH₂ --.

RB1 The residue was recrystallised from an ethyl acetate/petroleum ethermixture to give the desired product as the free base, the melting pointof which is given in the last column of Table RB.

RB2 The residue was characterised by converting a portion of it into itsoxalate salt, the melting point of which is given in the last column ofTable RB.

RB3 The residue was purified by hydrochloride salt formation. Themelting point of this salt is given in the last column of Table RB.

RB4 The residue was used as the starting material for the next stagewithout being characterised.

RB5 The residue was characterised by converting a portion of it into itshydrochloride salt the melting point of which is given in the lastcolumn of Table RB.

RB6 The reaction mixture was filtered and the volume reduced to half.The desired product precipitated and was collected by filtration. Themelting point is given in the last column of Table RB.

RB7 The residue was purified by flash chromatography to give the desiredproduct which was used without being further characterised.

RB8 The product was recrystallised from petroleum ether (b.p. 60°-80°C.).

RB9 The residue from the reaction mixture was freed of trimethylborateby azeotropic distillation with methanol and partitioned between waterand dichloromethane. The extract yielded the desired product which wasused without further purification.

RB10 The desired product precipitated from the reaction mixture oncooling. The product was washed with methanol and air dried. Its meltingpoint is given in Table RB.

RB11 Water was added to the reaction mixture and the desired productprecipitated on cooling. Its melting point is given in Table RB.

RB12 The reaction mixture was acidified with 5N hydrochloric acid andthe resulting solid collected by filtration. The solid was basified withaqueous sodium hydroxide solution and the resulting mixture extractedwith ether. The ether extract yielded the desired product which was usedwithout further purification.

                                      TABLE RB                                    __________________________________________________________________________    Ex  OR.sub.3                                                                          R.sub.4                                                                           E   G     SM  a  b  c  d Note                                                                              mp                                   __________________________________________________________________________    RB1 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-bromo-                                                                            CA1 5.8                                                                              250                                                                              1.6                                                                              (a)                                                                             RB1 112-114                                              phenyl                                                        RB2 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-chloro-                                                                           CA2 8.7                                                                              300                                                                              2.9                                                                              (a)                                                                             RB2 191                                                  phenyl                   (dec)                                RB3 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  4-fluoro-                                                                           CA3 7.9                                                                              30 2.6                                                                              (a)                                                                             RB2 193-194                                              phenyl                   (dec)                                RB4 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-methyl-                                                                           CA4 9.3                                                                              180                                                                              3.2                                                                              (a)                                                                             RB5 227-228                                              phenyl                                                        RB5 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-fluoro-                                                                           CA7 16 128                                                                              5.6                                                                              (b)                                                                             RB3 251                                                  phenyl                   (dec)                                RB6 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  3-tri-                                                                              CT1 15 100                                                                              1.5                                                                              (c)                                                                             RB5 198-201                                              fluoro-                                                                       methyl-                                                                       phenyl                                                        RB7 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.2                                                                  4-chloro-                                                                           CT2 10 200                                                                              1.8  RB6 132-133                                              phenyl                                                        RB8 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.4                                                                  phenyl                                                                              CT4 3.4                                                                              75 0.8                                                                              (c)                                                                             RB3 238-240                              RB9 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.5                                                                  4-chloro-                                                                           CT5 10.5                                                                             250                                                                              5  (c)                                                                             RB7                                                      phenyl                                                        RB10                                                                              7-OMe                                                                             6-OMe                                                                             W   phenyl                                                                              CT8 28 200                                                                              3.7                                                                              (c)                                                                             RB8 89-91                                RB11                                                                              7-OMe                                                                             6-Br                                                                              (CH.sub.2).sub.3                                                                  phenyl                                                                              CA12                                                                              4.2                                                                              100                                                                              2  (c)                                                                             RB4                                      RB12                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.4                                                                  4-methoxy                                                                           CT7 7.0                                                                              100                                                                              1  (c)                                                                             RB3 208-212                                              phenyl                                                        RB13                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  3,4-di-                                                                             CT6 10 200                                                                              4.8   RB10                                                                             101-103                                              chloro-                                                                       phenyl                                                        RB14                                                                              7-OMe                                                                             6-F (CH.sub.2).sub.3                                                                  phenyl                                                                              CA16                                                                              8.6                                                                              100                                                                              1.1                                                                              (c)                                                                             RB4                                      RB15                                                                              5-OMe                                                                             H   (CH.sub.2).sub.3                                                                  4-chloro-                                                                           CT9 4.3                                                                              75 0.5  RB4                                                      phenyl                                                        RB16                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.2                                                                  phenyl                                                                              CT10                                                                              2.1                                                                              30 0.35  RB11                                                                             97-99                                RB17                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.4                                                                  4-chloro-                                                                           CT3 4.2                                                                              100                                                                              2.85 RB9                                                      phenyl                                                        RB18                                                                              7-OMe                                                                             6-Cl                                                                              (CH.sub.2).sub.3                                                                  phenyl                                                                              CA9 5.8                                                                              100                                                                              0.7  RB9                                      RB19                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.5                                                                  phenyl                                                                              CT11                                                                              11 500                                                                              22.5 RB9                                      RB20                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-    CA17                                                                              6.2                                                                              25 1.9                                                                              (a)                                                                             RB4                                                      naphthyl                                                      RB21                                                                              7-OMe                                                                             6-Cl                                                                              W   phenyl                                                                              CA18                                                                              8  100                                                                              2.0                                                                              (b)                                                                             RB5 240                                                                           (dec)                                RB22                                                                              8-OMe                                                                             5-Cl                                                                              (CH.sub.2).sub.3                                                                  phenyl                                                                              CA19                                                                              10 100                                                                              1.5  RB9                                      RB23                                                                              6-OMe                                                                             7-Cl                                                                              (CH.sub.2).sub.3                                                                  phenyl                                                                              CT12                                                                              23.6                                                                             400                                                                              17    RB12                                    RB24                                                                              7-OMe                                                                             5-Cl                                                                              (CH.sub.2).sub.3                                                                  phenyl                                                                              CT14                                                                              10.5                                                                             150                                                                              1.5  RB9                                              6-OMe                                                                 RB25                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-chloro-                                                                           CA27                                                                              5  30 1.8                                                                              (c)                                                                             RB4                                                      phenyl                                                        RB26                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.5                                                                  phenyl                                                                              CA33                                                                              5.5                                                                              50 4    RB9                                      __________________________________________________________________________

EXAMPLES RC ##STR31##

A solution of a compound of formula VII in which OR₅ is the group OR₃ asidentified in Table RC and R₄, E and G are as identified in Table RC (ag, prepared as described in the Example identified in column SM of TableRC) in glacial acetic acid (b ml) and methanol (c ml) at 0° C. wastreated with sodium cyanoborohydride (d g). The mixture was stirred atambient temperature for e hours to give a compound of formula VI inwhich OR₃, R₄, E and G are as identified in Table RC. The reactionmixture was then treated as described in the Notes to Table RC.

NOTES TO TABLE RC

The abbreviation "OBz" represents benzyloxy and W represents --CH₂ CMe₂CH₂ --.

RC1 The volume of the reaction mixture was reduced by evaporation andthe residue partitioned between water and dichloromethane. The organiclayer was washed with concentrated aqueous ammonia solution and brineand then dried. Removal of the solvent gave a residue which was usedwithout further purification.

RC2 The reaction mixture was poured into water and the resulting mixtureextracted with dichloromethane. The extract was washed with brine anddried. Removal of the solvent gave a solid which was triturated withpetroleum ether (bp 60°-80° C.), recrystallised from ethanol and thendissolved in dichloromethane. The solution was washed with concentratedaqueous ammonia solution and dried. Removal of the solvent gave thedesired product.

RC3 The volume of the reaction mixture was reduced by evaporation andthe residue partitioned between water and dichloromethane. The organiclayer was washed with concentrated aqueous ammonia solution and brineand then dried. Removal of the solvent gave a residue which wastriturated with a mixture of light petroleum ether and ether to give thedesired product, the melting point of which was 100°-102° C.

RC4 The volume of the reaction mixture was reduced by evaporation andthe residue partitioned between water and dichloromethane. The organiclayer was washed with concentrated aqueous ammonia solution and brine,dried, decolourised and then the solvent was removed to give a syrupwhich crystallised on standing. The product was washed with ether anddried (mp 109°-111° C.).

RC5 The reaction mixture was diluted with dichloromethane and theresulting organic layer was washed with concentrated aqueous ammoniasolution and dried. Evaporation yielded the desired product as a syrupwhich was used in the next stage without further purification.

RC6 The reaction mixture was poured into water and extracted withdichloromethane. The organic layer was washed with concentrated aqueousammonia solution and brine and then dried. The dried organic layeryielded the desired product on evaporation which was used in the nextstage without further purification.

RC7 Water was added to the reaction mixture and the mixture basifiedwith aqueous ammonia solution and extracted with ether. The extractyielded the desired product which was used without further purification.

RC8 The reaction mixture was added to ice/water, basified with aqueousammonia solution and extracted with ether. Ethereal oxalic acid solventwas added to give the desired product as an oxalate salt which was driedat 55° C. in vacuo.

RC9 After 24 hours unreacted starting material was detected. A furtherportion of sodium cyanoborohydride (0.2 g) was added and the mixturestirred for 2 hours. The reaction mixture was partitioned betweendichloromethane and water. The organic layer was washed withconcentrated aqueous ammonia solution and yielded the desired productwhich was used without further purification.

RC10 After 24 hours unreacted starting material was detected. A furtherportion of sodium cyanoborohydride (0.2 g) was added and the mixturestirred for 24 hours. The reaction mixture was partitioned betweendichloromethane and concentrated aqueous ammonia solution. The organiclayer yielded the desired product which was used without furtherpurification.

RC11 The reaction mixture was initially stirred at 0°-5° C. for 2 hoursand then stirred at ambient temperature for 24 hours. The reactionmixture was poured onto a mixture of ice and water, basified by theaddition of concentrated aqueous ammonia solution and extracted withdichloromethane. The extract yielded the desired product which was usedwithout further purification.

RC12 The reaction mixture was poured into water, basified with aqueousammonia solution and extracted with ethyl acetate. The extract yielded agum which was dissolved in ether and treated with ethereal oxalic acidto give the desired product as an oxalate salt which was dried in vacuo.

RC13 The reaction mixture was poured into aqueous ammonia solution andextracted with ethyl acetate. The extracts were washed with aqueousammonia solution and brine, then dried and concentrated to give thedesired product which was used without further purification.

RC14 The volume of the reaction mixture was reduced by evaporation andthe residue partitioned between dichloromethane and concentrated aqueousammonia solution. The organic layer was dried, filtered and evaporatedin vacuo to yield an oil which was dissolved in propan-2-ol and treatedwith 48% aqueous hydrobromic acid. Evaporation yielded a solidhydrobromide salt which was recrystallised from ether.

RC15 The reaction mixture was initially stirred at 0°-5° C. for 2 hoursand then stirred at ambient temperature for 24 hours. The reactionmixture was poured onto a mixture of ice and water, basified by theaddition of concentrated aqueous ammonia solution and extracted withdichloromethane. The extracts yielded a residue which was dissolved inpropan-2-ol (50 ml). 48% Aqueous hydrobromic acid (25 ml) was added. Themixture was dried by azeotropic distillation with propan-2-ol andcrystallised from ether to give the desired product as a hydrobromidesalt (m.p. 227°-233° C.).

RC16 The reaction mixture was treated in a manner similar to thatdescribed in Note RC6, but the product was then dissolved in propan-2-oland treated with 48% aqueous hydrobromic acid solution. The solution wascooled and scratched to yield a solid which was filtered and dried toyield the hydrobromide salt.

RC17 The reaction mixture was poured onto water and extracted withdichloromethane. The organic layer was washed with dilute aqueousammonia solution, then with water, then was dried over magnesiumsulphate, filtered and concentrated in vacuo. The residue was dissolvedin ether and hydrogen chloride was bubbled through. The resultingprecipitate was collected by filtration, washed with ether and dried invacuo, yielding the desired product as a hydrochloride salt.

                                      TABLE RC                                    __________________________________________________________________________    Ex  OR.sub.3                                                                          R.sub.4                                                                           E   G     SM  a  b  c  d  e  Notes                                __________________________________________________________________________    RC1 7-OMe                                                                             6-F (CH.sub.2).sub.3                                                                  4-chloro-                                                                           CA5 6  50 25 2.2                                                                              24 RC1                                                  phenyl                                                        RC2 7-OMe                                                                             6-F (CH.sub.2).sub.3                                                                  4-bromo-                                                                            CA6 8.3                                                                              50 25 2.7                                                                              16 RC2                                                  phenyl                                                        RC3 7-OMe                                                                             6-F (CH.sub.2).sub.3                                                                  2,4-di-                                                                             CA8 4.8                                                                              40 20 1.6                                                                              24 RC3                                                  chloro-                                                                       phenyl                                                        RC4 7-OMe                                                                             6-F (CH.sub.2).sub.2                                                                  2,4-di                                                                              CQ  9.7                                                                              100                                                                              50 3.4                                                                              16  RC16                                                chloro-                                                                       phenyl                                                        RC5 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  4-bromo-                                                                            CA10                                                                              13 100                                                                              50 4.1                                                                              72 RC4                                                  phenyl                                                        RC6 7-OMe                                                                             6-Cl                                                                              (CH.sub.2).sub.3                                                                  2-chloro-                                                                           CA13                                                                              4.3                                                                              30 15 1.5                                                                              24 RC5                                                  phenyl                                                        RC7 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-tri-                                                                              CA14                                                                              5  40 20 3.2                                                                              16 RC6                                                  fluoro-                                                                       methyl-                                                                       phenyl                                                        RC8 7-OMe                                                                             6-F (CH.sub.2).sub.3                                                                  2-chloro-                                                                           CA15                                                                              9.4                                                                              50 25 3.4                                                                              20 RC6                                                  phenyl                                                        RC9 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2,4-di-                                                                             CA21                                                                              4  28 14 2  2  RC7                                                  chloro-                                                                       phenyl                                                        RC10                                                                              7-OMe                                                                             H   (CH.sub.2).sub.2                                                                  2-chloro-                                                                           CP  2.4                                                                              20 10 0.9                                                                              16  RC13                                                phenyl                                                        RC11                                                                              7-OMe                                                                             H   (CH.sub.2).sub.3                                                                  2-chloro-                                                                           CA22                                                                              5.2                                                                              42 21 2.4                                                                              3  RC8                                                  phenyl                                                        RC12                                                                              7-OMe                                                                             6-Me                                                                              (CH.sub.2).sub.3                                                                  2-chloro-                                                                           CA23                                                                              5.78                                                                             55 27.5                                                                             2.1                                                                              1   RC12                                                phenyl                                                        RC13                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2,4-di-                                                                             CA30                                                                              4.4                                                                              20 10 1.2                                                                              24 RC9                                                  chloro-                                                                       phenyl                                                        RC14                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.2                                                                  2-chloro-                                                                           CA28                                                                              6.3                                                                              40 20 1.9                                                                              24  RC14                                                phenyl                                                        RC15                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.2                                                                  1-    CA29                                                                              11 64 32 3.2                                                                              120                                                                              RC7                                                  naphthyl                                                      RC16                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-methoxy                                                                           CA25                                                                              6  40 20 1.8                                                                              24  RC10                                                phenyl                                                        RC17                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  3-methoxy                                                                           CA26                                                                              6.65                                                                             50 25 2.65   RC11                                                phenyl                                                        RC18                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  4-tri-                                                                              CA31                                                                              4.1                                                                              30 15 1.1                                                                              1   RC13                                                fluoro-                                                                       methoxy-                                                                      phenyl                                                        RC19                                                                              7-OMe                                                                             6-F (CH.sub.2).sub.3                                                                  2-bromo-                                                                            CA35                                                                              5  30 15 1.7                                                                              16 RC6                                                  phenyl                                                        RC20                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  4-bi- CA11                                                                              4.7                                                                              30 15 1.49                                                                             24  RC17                                                phenylyl                                                      RC21                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  3-chloro-                                                                           CA24                                                                              8.6                                                                              50 25 3.5                                                                              5  RC7                                                  phenyl                                                        RC22                                                                              7-OMe                                                                             6-Ph                                                                              (CH.sub.2).sub.3                                                                  2-chloro-                                                                           CA37                                                                              7.8                                                                              53 26 2.94                                                                             2   RC15                                                phenyl                                                        RC23                                                                              7-OBz                                                                             6-OMe                                                                             W   2-chloro-                                                                           CA36                                                                              9.2                                                                              100                                                                              50 2.6                                                                              16 RC6                                                  phenyl                                                        __________________________________________________________________________

EXAMPLES CA ##STR32##

A mixture of a compound of formula XII in which OR₅, R₄, E and G are asidentified in Table CA (a g, prepared as described in the Exampleidentified in column SM of Table CA), phosphorus oxychloride (b ml) andacetonitrile (c ml) was heated under reflux. After heating for d hoursthe mixture was basified with aqueous ammonia solution and extractedwith the solvent identified in column f of Table CA (a=ethyl acetate,b=dichloromethane, c=ether). The extract yielded a residue which wastreated as described in the Notes to Table CA to give a compound offormula VII in which OR₅, R₄, E and G are as identified in Table CA.

NOTES TO TABLE CA

The abbreviation "OBz" represents benzyloxy. In column E of Table CA, Wrepresents --CH₂.CMe₂.CH₂ --.

CA1 The residue was used as the starting material for the next stagewithout further purification. The melting point of the residue is givenin the last column of Table CA.

CA2 The residue was recrystallised from petroleum ether (b.p. 60°-80°C.) to give the desired product, the melting point of which is given inthe last column of Table CA.

CA3 The residue was recrystallised from propan-2-ol to give the desiredproduct, the melting point of which is given in the last column of TableCA.

CA4 The residue was used without being characterised.

CA5 The residue was treated with a 2:1 mixture of propan-2-ol and etherto yield the product as a pale yellow solid, the melting point of whichis given in the last column of Table CA.

CA6 The reaction mixture was poured into ice/water, basified withaqueous sodium hydroxide solution and extracted with ether. The extractyielded a residue was taken up in a hot mixture of ether andcyclohexane. A solid precipitated on cooling which was recrystallisedfrom propan-2-ol to give the desired product, the melting point of whichis given in the last column of Table CA.

CA7 The residue was treated with cold propan-2-ol. The desired productwas collected by filtration. The melting point is given in the lastcolumn of Table CA.

CA8 The residue was crystallised from methanol. The melting point of thedesired product is given in the last column of Table CA.

CA9 The residue was treated with ether and the resulting mixturefiltered. The desired product was obtained from the filtrate and usedwithout further purification.

CA10 The residue was triturated with petroleum ether (b.p. 40°-60° C.)to give the desired product, the melting point of which is given in thelast column of Table CA.

CA11 The residue was treated with acetonitrile. A solid was separated byfiltration and the filtrate concentrated to give a gum which waspurified by flash chromatography. A sample of the resulting product wasrecrystallised from propan-2-ol to give the desired product, the meltingpoint of which is given in Table CA.

CA12 The residue was triturated with petroleum ether (b.p. 60°-80° C.)to give the desired product, the melting point of which is given in thelast column of Table CA.

CA13 The residue was triturated with petroleum ether (b.p. 60°-80° C.)and recrystallised from propan-2-ol.

CA14 The residue was purified by flash chromatography to yield the solidproduct, the melting point of which is given in Table CA.

CA15 The residue was extracted with boiling petroleum ether (b.p.60°-80° C.). The extract gave a residue which was recrystallised frompropan-2-ol to give the desired product, the melting point of which isgiven in the last column of Table CA.

CA16 The residue was treated with a 1:3 mixture of ether and propan-2-olto give the desired product as a solid, the melting point of which isgiven in Table CA.

CA17 The residue was crystallised from ethanol. A sample (1 g) wasrecrystallised from ethanol to give a solid, the melting point of whichis given in the last column of Table CA.

CA18 The extract was washed with dilute aqueous hydrochloric acid. Thewashings were basified and extracted with ethyl acetate. The extractyielded the desired product which was used without further purification.

CA19 The extract was washed with brine, dried over magnesium sulphate,decolourised with charcoal, filtered and the solvent removed byevaporation to yield a solid. The solid was recrystallised frompropan-2-ol to yield7-benzyloxy-6-methoxy-[1-(2-methylthiophenyl)cyclobutyl]dihydroisoquinoline.

CA20 After heating for 2 hours, the reaction mixture was poured ontoice/water and basified with concentrated aqueous ammonia solution. Thebasic solution was extracted with ethyl acetate and the extracts washedwith brine, dried over magnesium sulphate and filtered. The solvent wasremoved in vacuo to yield a gum which was used without furtherpurification.

CA21 After heating for d hours, the solvent was removed in vacuo and theresidue dissolved in ethyl acetate. A slight excess of aqueous ammoniasolution was added. The organic layer yielded a gum which was usedwithout further purification.

CA22 The extract was washed with dilute aqueous sodium hydroxidesolution and brine. The extract yielded a residue which was used withoutfurther purification.

                                      TABLE CA                                    __________________________________________________________________________    Ex  OR.sub.5                                                                          R.sub.4                                                                           E   G    SM a  b  c  d  f Note                                                                              mp                                  __________________________________________________________________________    CA1 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-bromo-                                                                           D1 7.7                                                                              11.3                                                                             80 2.5                                                                              (a)                                                                             CA1 125-127                                             phenyl                                                        CA2 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-chloro-                                                                          D2 12 20 200                                                                              2.5                                                                              (b)                                                                             CA1 135-138                                             phenyl                                                        CA3 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  4-fluoro-                                                                          D3 12 21 145                                                                              2.5                                                                              (a)                                                                             CA1 100-101                                             phenyl                                                        CA4 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-methyl-                                                                          D4 15.1                                                                             26.5                                                                             185                                                                              2.5                                                                              (a)                                                                             CA2 105-106                                             phenyl                                                        CA5 7-OMe                                                                             6-F (CH.sub.2).sub.3                                                                  4-chloro-                                                                          E1 16 13 150                                                                              40 (a)                                                                             CA3 84-86                                               phenyl                                                        CA6 7-OMe                                                                             6-F (CH.sub.2).sub.3                                                                  4-bromo-                                                                           E2 9.5                                                                              6.5                                                                              100                                                                              48 (a)                                                                             CA4                                                     phenyl                                                        CA7 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-fluoro-                                                                          D5 25 43.7                                                                             300                                                                              2.5                                                                              (a)                                                                             CA1 104-106                                             phenyl                                                        CA8 7-OMe                                                                             6-F (CH.sub.2).sub.3                                                                  2,4-di-                                                                            E5 8.3                                                                              6  75 40 (a)                                                                             CA3 117-119                                             chloro-                                                                       phenyl                                                        CA9 7-OMe                                                                             6-Cl                                                                              (CH.sub.2).sub.3                                                                  phenyl                                                                             E6 64.3                                                                             52 300                                                                              48 (a)                                                                             CA5 97-99                               CA10                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  4-bromo-                                                                           E11                                                                              17.5                                                                             8  100                                                                              20 (a)                                                                             CA4                                                     phenyl                                                        CA11                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  4-bi-                                                                              E39                                                                              12.5                                                                             8.5                                                                              100                                                                              18 (a)                                                                             CA20                                                    phenylyl                                                      CA12                                                                              7-OMe                                                                             6-Br                                                                              (CH.sub.2).sub.3                                                                  phenyl                                                                             E14                                                                              10 50 100                                                                              42   CA6 119-120                             CA13                                                                              7-OMe                                                                             6-Cl                                                                              (CH.sub.2).sub.3                                                                  2-chloro-                                                                          E16                                                                              18 13 100                                                                              48 (a)                                                                             CA7 141-143                                             phenyl                                                        CA14                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-tri-                                                                             E17                                                                              15 10.5                                                                             150                                                                              40 (a)                                                                             CA3 141-143                                             fluoro-                                                                       methyl-                                                                       phenyl                                                        CA15                                                                              7-OMe                                                                             6-F (CH.sub.2).sub.3                                                                  2-chloro-                                                                          E18                                                                              24 18.5                                                                             150                                                                              36 (a)                                                                             CA3 125-127                                             phenyl                                                        CA16                                                                              7-OMe                                                                             6-F (CH.sub.2).sub.3                                                                  phenyl                                                                             E19                                                                              18 15.5                                                                             150                                                                              36 (a)                                                                             CA4                                     CA17                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-   E23                                                                              6  9.5                                                                              65 2.5                                                                              (a)                                                                             CA8 128-129                                             naphthyl                                                      CA18                                                                              7-OMe                                                                             6-Cl                                                                              W   phenyl                                                                             E24                                                                              15 7.9                                                                              100                                                                              24 (c)                                                                             CA9                                     CA19                                                                              8-OMe                                                                             5-Cl                                                                              (CH.sub.2).sub.3                                                                  phenyl                                                                             E27                                                                              20.6                                                                             16.8                                                                             150                                                                              5  (a)                                                                             CA10                                                                              129-132                             CA20                                                                              7-OMe                                                                             6-Cl                                                                              (CH.sub.2).sub.3                                                                  2-bromo-                                                                           D6 10.5                                                                             15.1                                                                             250                                                                              48 (a)                                                                             CA11                                                    phenyl                                                        CA21                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2,4-di-                                                                            E28                                                                              12.7                                                                             11 50 8  (a)                                                                             CA12                                                                              115-117                                             chloro-                                                                       phenyl                                                        CA22                                                                              7-OMe                                                                             H   (CH.sub.2).sub.3                                                                  2-chloro-                                                                          E29                                                                              34.2                                                                             29 200                                                                              23 (c)                                                                             CA4                                                     phenyl                                                        CA23                                                                              7-OMe                                                                             6-Me                                                                              (CH.sub.2).sub.3                                                                  2-   D7 19 30.8                                                                             185                                                                              5  (a)                                                                             CA17                                                                              126-128                                             chloro-                                                                       phenyl                                                        CA24                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  3-chloro-                                                                          E31                                                                              12.9                                                                             11 50 24 (c)                                                                             CA13                                                                              103-104                                             phenyl                                                        CA25                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-   E33                                                                              16.2                                                                             10 100                                                                              2  (a)                                                                             CA14                                                                              107-108                                             methoxy-                                                                      phenyl                                                        CA26                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  3-   E34                                                                              17 20 150                                                                              5  (b)                                                                             CA15                                                                              107-109                                             methoxy-                                                                      phenyl                                                        CA27                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-chloro-                                                                          E36                                                                              21 25 150                                                                              6  (a)                                                                             CA14                                                                              112-114                                             phenyl                                                        CA28                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.2                                                                  2-chloro-                                                                          E35                                                                              15.5                                                                             10 75 18 (a)                                                                             CA17                                                                              121-123                                             phenyl                                                        CA29                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.2                                                                  1-   E45                                                                              14.1                                                                             25 200                                                                              1.5                                                                              (a)                                                                             CA21                                                                              ND                                                  naphthyl                                                      CA30                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2,4-di-                                                                            E37                                                                              23 13.5                                                                             150                                                                              4  (a)                                                                             CA16                                                                              118-119                                             chloro-                                                                       phenyl                                                        CA31                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  4-tri-                                                                             D9 7.9                                                                              9.2                                                                              55 5  (a)                                                                             CA1 158-161                                             fluoro-                                                                       methoxy-                                                                      phenyl                                                        CA32                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  2-methyl                                                                           E38                                                                              4.7                                                                              3  30 3  (a)                                                                             CA19                                                                              ND                                                  thio                                                                          phenyl                                                        CA33                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.5                                                                  phenyl                                                                             E40                                                                              26.7                                                                             17 100                                                                              2.5                                                                              (a)                                                                             CA14                                                                              96-98                               CA34                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub. 2).sub.4                                                                 2-chloro-                                                                          E41                                                                              12.7                                                                             7.7                                                                              100                                                                              16 (a)                                                                             CA4 ND                                                  phenyl                                                        CA35                                                                              7-OMe                                                                             6-F (CH.sub.2).sub.3                                                                  2-bromo-                                                                           E42                                                                              10 7  100                                                                              48 (a)                                                                             CA3 129-130                                             phenyl                                                        CA36                                                                              7-OBz                                                                             6-OMe                                                                             W   2-   E43                                                                              14.6                                                                             8.5                                                                              100                                                                              20 (a)                                                                             CA22                                                                              ND                                                  chloro-                                                                       phenyl                                                        __________________________________________________________________________

EXAMPLE CA37

A mixture ofN-[2-(2-methoxy-5-biphenylyl)ethyl]-1-(2-chlorophenyl)cyclobutanecarboxamide (12.5 g, prepared as described in Example E30), phosphorusoxychloride (25 ml) and acetonitrile (150 ml) was heated under refluxfor 6 hours. The solvent was removed by distillation and the residueadded to a mixture of ice and water. The mixture was extracted withdichloromethane to yield a solid which was recrystallised frompropan-2-ol to give1-[1-(2-chlorophenyl)cyclobutyl]-7-methoxy-6-phenyl-3,4-dihydroisoquinoline,m.p. 149°-152° C.

EXAMPLE CP

A mixture ofN-[2-(4-methoxyphenyl)ethyl]-1-(2-chlorophenyl)cyclopropanecarboxamide(2 g, prepared in a similar manner to that described in Example D8) andpolyphosphate ester (20 ml) was gently heated for 12 hours. The mixturewas poured into water and washed with ether, then ethyl acetate. Theaqueous phase was basified with aqueous ammonia solution and extractedwith ethyl acetate. The extract yielded a solid which was recrystallisedfrom cyclohexane to give1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-3,4-dihydroisoquinoline.

EXAMPLE CO

A mixture ofN-[2-(3-fluoro-4-methoxyphenyl)ethyl]-1-(2,4-dichlorophenyl)cyclopropanecarboxamide(19.7 g, prepared in a similar manner to that described in Example E4),52% polyphosphate ester in chloroform (200 g) was heated under refluxfor 52 hours, then cooled and poured onto ice. The organic layer wasseparated, the aqueous layer extracted with dichloromethane and thecombined organic layers were basified by addition of aqueous ammoniasolution, washed with brine, dried over magnesium sulphate and filtered.The solvent was removed in vacuo to yield a solid which was trituratedwith petroleum ether (b.p. 40°-60° C.) and propan-2-ol. The solid wascollected by filtration and dried to yield1-[1-(2,4-dichlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-3,4-dihydroisoquinoline(10.3 g), m.p. 151°-154° C.

EXAMPLES CT ##STR33##

A mixture of a compound of formula XII in which OR₅, R₄, E and G are asidentified in Table CT (a g, prepared as described in the Exampleidentified in column SM of Table CT), phosphorus oxychloride (b ml) andtoluene (c ml) was heated on a steam bath for d hours. The mixture waspoured into ice/water, basified with concentrated aqueous ammoniasolution and extracted with the solvent identified in column e of TableCT (a=ethyl acetate, b=ether). The extract yielded a residue which wastreated as described in the Notes to Table CT to give a compound offormula VII in which OR₅, R₄, E and G are as identified in Table CT.

NOTES TO TABLE CT

The abbreviation "OBz" represents benzyloxy. In column E of Table CT, Wrepresents --CH₂.CMe₂.CH₂ --.

CT1 The residue was treated with a mixture of ether and petroleum ether.The resulting solid was collected by filtration. Its melting point isgiven in the last column of Table CT.

CT2 The residue was crystallised from a 4:1:2 mixture of ether, ethylacetate and petroleum ether to give the desired product, the meltingpoint is given in the last column of Table CT.

CT3 The residue was used in the next stage without further purification.The melting point is given in the last column of Table CT.

CT4 The toluene was removed from the reaction mixture by evaporation andthe residue poured into ice/water. The solution was basified withaqueous ammonia solution and extracted with ether. The extract yieldedthe desired product, the melting point of which is given in the lastcolumn of Table CT.

CT5 The residue was crystallised from ether to give the desired product.The melting point is given in the last column of Table CT.

CT6 The residue was crystallised from a mixture of ether and petroleumether. The resulting solid was collected by filtration. Its meltingpoint is given in the last column of Table CT.

CT7 The residue was used in the next stage without further purification.

CT8 The residue was purified by flash chromatography to give the desiredproduct. The melting point is given in the last column of Table CT.

CT9 The residue was treated with a mixture of ether and petroleum ether.The resulting solid was collected by filtration. The product was usedwithout further treatment.

CT10 The residue was taken up in ether and the solution dried. Anethereal solution of oxalic acid was added to give the oxalate saltwhich was washed with ether and partitioned between aqueous ammoniasolution and ether. The ether layer gave the desired product in the formof its free base as an oil which was used without further purification.

CT11 The residue was taken up in ether and an ethereal solution ofoxalic acid added to give the oxalate salt which was washed with ether,basified with 30% aqueous potassium hydroxide solution and extractedwith ether. The extract yielded an oil which was used without furtherpurification.

                                      TABLE CT                                    __________________________________________________________________________    Ex  OR.sub.5                                                                          R.sub.4                                                                           E   G     SM a  b  c  d  e Note                                                                              mp                                 __________________________________________________________________________    CT1 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  3-trifluoro-                                                                        E3 35 23.8                                                                             200                                                                              16 (a)                                                                             CT1  98-100                                            methyl                                                                        phenyl                                                        CT2 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.2                                                                  4-chloro                                                                            E7 30 16.6                                                                             200                                                                              8  (b)                                                                             CT2 91-92                                              phenyl                                                        CT3 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.4                                                                  4-chloro                                                                            E8 34 23.8                                                                             200                                                                              8  (b)                                                                             CT3 106-107                                            phenyl                                                        CT4 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.4                                                                  phenyl                                                                              E9 36 27.9                                                                             200                                                                              1    CT4 112-114                            CT5 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.5                                                                  4-chloro                                                                            E10                                                                              17 11.3                                                                             100                                                                              8  (b)                                                                             CT5 135-136                                            phenyl                                                        CT6 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  3,4-di-                                                                             E12                                                                              39 26.1                                                                             200                                                                              8  (b)                                                                             CT6 111-112                                            chloro                                                                        phenyl                                                        CT7 7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.4                                                                  4-    E13                                                                              14 9.5                                                                              100                                                                              2  (b)                                                                             CT5 88-89                                              methoxy                                                                       phenyl                                                        CT8 7-OMe                                                                             6-OMe                                                                             W   phenyl                                                                              E15                                                                              30 14.9                                                                             200                                                                              6  (a)                                                                             CT7                                    CT9 5-OMe                                                                             H   (CH.sub.2).sub.3                                                                  4-chloro                                                                            E20                                                                              13 35 100                                                                              30 (a)                                                                             CT8 111-112                                            phenyl                                                        CT10                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.2                                                                  phenyl                                                                              E21                                                                              26 22 100                                                                              1  (a)                                                                             CT3 141-144                            CT11                                                                              7-OMe                                                                             6-OMe                                                                             (CH.sub.2).sub.5                                                                  phenyl                                                                              E22                                                                              29 14.8                                                                             200                                                                              20 (a)                                                                             CT9                                    CT12                                                                              6-OMe                                                                             7-Cl                                                                              (CH.sub.2).sub.3                                                                  phenyl                                                                              E25                                                                              25.7                                                                             207                                                                              300                                                                              5  (b)                                                                             CT7                                    CT13                                                                              7-OMe                                                                             H   (CH.sub.2).sub.3                                                                  phenyl                                                                              E44                                                                              24 22 200                                                                              72 (b)                                                                              CT10                                  CT14                                                                              7-OMe                                                                             5-Cl                                                                              (CH.sub.2).sub.3                                                                  phenyl                                                                              E26                                                                              12.5                                                                             9.6                                                                              75 2.5                                                                              (a)                                                                             CT7                                            6-OMe                                                                 CT15                                                                              7-OBz                                                                             6-OMe                                                                             (CH.sub.2).sub.3                                                                  phenyl                                                                              E32                                                                              32.9                                                                             22 200                                                                              3.5                                                                              (b)                                                                              CT11                                  __________________________________________________________________________

EXAMPLES D ##STR34##

A 1-arylcycloalkanecarbonyl chloride of formula XV in which E and G areas identified in Table D, (a g prepared as described in the Exampleidentified in column SM of Table D) was added dropwise at 0° C. to astirred solution of a phenethylamine of formula XVII in which OR₅ and R₄are as identified in Table D, (b g) and triethylamine (c ml) in ether (dml) to form a compound of formula XII. After 16 hours the reactionmixture was poured into water and extracted with the solvent identifiedin column e of Table D (a=ethyl acetate, b=ether, c=dichloromethane).The extract yielded a residue which was treated as described in theNotes (Nb) to Table D.

NOTES (Nb) TO TABLE D

D1 The residue was used without further purification Its melting pointis given in the last column of Table D.

D2 The residue was washed with petroleum ether (b.p 60°-80° C.). Itsmelting point is given in the last column of Table D.

D3 The residue was a glass, the melting point of which was notdetermined.

D4 The ether in the reaction mixture was replaced by dichloromethane andthe reaction mixture poured into water and acidified with concentratedhydrochloric acid. Evaporation of the dichloromethane layer gave aresidue which was washed with ethanol and dried in vacuo. It was usedwithout further purification. Its melting point is given in Table D.

D5 The reaction mixture was stirred for two days and then poured intowater. The mixture was basified, stirred for 30 minutes, acidified,washed with ether, basified and extracted with ethyl acetate. Theextract yielded the desired product which was used without furtherpurification.

                                      TABLE D                                     __________________________________________________________________________    Ex                                                                              OR.sub.5                                                                          R.sub.4                                                                           E   G    SM  a  b  c  d  e Nb                                                                              mp                                     __________________________________________________________________________    D1                                                                              4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  2-bromo-                                                                           CL1 5.5                                                                              3.3                                                                              2.8                                                                              150                                                                              a D1                                                                              111-112                                              phenyl                                                          D2                                                                              4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  2-chloro                                                                           CL2 9  6.5                                                                              5.5                                                                              150                                                                              b D1                                                                              119-120                                              phenyl                                                          D3                                                                              4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  4-fluoro                                                                           CL3 15 11.6                                                                             9.8                                                                              150                                                                              b D2                                                                              83-84                                                phenyl                                                          D4                                                                              4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  2-methyl                                                                           CL4 11 8.7                                                                              7.4                                                                              150                                                                              a D3                                                     phenyl                                                          D5                                                                              4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  2-fluoro                                                                           CL5 16 15 11.6                                                                             250                                                                              a D1                                                                              119-120                                              phenyl                                                          D6                                                                              4-OMe                                                                             3-Cl                                                                              (CH.sub.2).sub.3                                                                  2-bromo                                                                            CL1 11 7.2                                                                              5.6                                                                              120                                                                              c D4                                                                              116-119                                              phenyl                                                          D7                                                                              4-OMe                                                                             3-Me                                                                              (CH.sub.2).sub.3                                                                  2-chloro                                                                           CL2 12.4                                                                             9.45                                                                             10.96                                                                            140                                                                              a D5                                                                              ND                                                   phenyl                                                          D8                                                                              4-OMe                                                                             H   (CH.sub. 2).sub.2                                                                 2-chloro                                                                           CL11                                                                              10 7  7.2                                                                              130                                                                              b D2                                                                              84-85                                                phenyl                                                          D9                                                                              4-OBz                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  4-tri-                                                                             CL20                                                                              5.26                                                                             5.55                                                                             5.8                                                                              50 b D1                                                                              ND                                                   fluoro                                                                        methoxy                                                                       phenyl                                                          __________________________________________________________________________

EXAMPLES E ##STR35##

A solution of a 1-arylcycloalkane carbonyl chloride of formula XV inwhich E and G are as identified in Table E (a g prepared as described inthe Example identified in column SM of Table E) in ether (b ml) wasadded dropwise to a stirred solution of a phenethylamine of formula XVIIin which OR₅ and R₄ are as identified in Table E (c g) and triethylamine(d ml) in ether (e ml) to form a compound of formula XII. When thereaction was complete water was added and the product was isolated andtreated as described in the Notes to Table E.

NOTES TO TABLE E

The abbreviation "OBz" represents benzyloxy. In column E of Table E, Wrepresents --CH₂.CMe₂.CH₂ --.

E1 The residue obtained by evaporation of the organic layer of thereaction mixture was triturated with petroleum ether and then used asthe starting material for the next stage without further purification.

E2 The residue obtained by evaporation of the organic layer of thereaction mixture was used without further purification.

E3 The residue obtained by evaporation of the organic layer of thereaction mixture was recrystallised from propan-2-ol.

E4 The residue obtained by evaporation of the organic layer of thereaction mixture was treated with a mixture of ether and petroleum etherand collected by filtration. The melting point is given in the lastcolumn of Table E.

E5 The solution of the phenethylamine was added to the solution of thecarbonyl chloride. The reaction mixture gave a precipitate which wascollected by filtration, washed with ether and water and dried in vacuoto give the desired product.

E6 The solution of the phenethylamine was added to the solution of thecarbonyl chloride. The product was isolated from the organic phase andused without further purification.

E7 The melting point of the product is given in the last column of TableE.

E8 The residue obtained by evaporation of the organic layer of thereaction mixture was triturated with petroleum ether to give the desiredproduct the melting point of which is given in the last column of TableE.

E9 The solution of the phenethylamine was added to the solution of thecarbonyl chloride. The product was isolated from the organic phase andits melting point is given is the last column of Table E.

E10 The reaction was conducted under nitrogen. After the addition of thewater, the reaction mixture was extracted with ethyl acetate and thedesired product isolated from the organic layer and recrystallised froma mixture of ethyl acetate and petroleum ether. Its melting point isgiven in the last column of Table E.

E11 The product precipitated after the addition of the water and wascollected, washed with water and dried in vacuo. Its melting point isgiven in the last column of Table E.

E12 The preparation of the phenethylamine starting material is given inExample P.

E13 After the addition of the water the reaction mixture was extractedwith ethyl acetate and the desired product isolated from the organiclayer and was used without further purification.

E14 The preparation of the phenethylamine starting material is given inExample Q. The aqueous mixture was extracted with ethyl acetate. Theorganic phase was washed with water, 2N hydrochloric acid, water and 2Naqueous sodium hydroxide solution. The extract yielded a residue whichwas recrystallised twice from propan-2-ol to give the desired product,the melting point of which is given in the last column of Table E.

E15 Ethyl acetate was added after the water and the desired product wasobtained from the organic layer and treated with a mixture of ether andpetroleum ether. The product was used without further purification.

E16 After the addition of the water, the reaction mixture was extractedwith ethyl acetate and the organic phase was washed with 1N hydrocloricacid, water, then 1N aqueous sodium hydroxide solution, dried overmagnesium sulphate and the solvent removed to give the desired productwhich was used without further purification.

E17 After the addition of water, the mixture was stirred for 30 minutes,then the organic layer separated, washed with dilute aqueous sodiumhydroxide solution, dilute aqueous hydrochloric acid and then brine,dried and filtered. The filtrate yielded a gum which was purified bycolumn chromatography, using a 1:3 mixture of ethyl acetate andpetroleum ether as eluant, to yield the desired product.

E18 After the addition of water, the mixture was stirred for 1 hour,then the organic layer was separated and the aqueous layer was extractedwith ether. The combined organic layers were washed with dilutehydrochloric acid, dilute sodium hydroxide, and brine, and were thendried over magnesium sulphate and filtered. The solvent was removed fromthe filtrate in vacuo to yield a solid which was triturated withpetroleum ether (b.p. 60°-80° C.) and collected by filtration to yieldthe desired product.

E19 After the addition of water, the organic layer was separated and theaqueous layer was extracted with ether. The combined organic layers werewashed with dilute hydrochloric acid, dilute sodium hydroxide, andbrine, and were then dried over magnesium sulphate and filtered. Thesolvent was removed from the filtrate in vacuo to yield a gum which wasused without further purification.

                                      TABLE E                                     __________________________________________________________________________    Ex  OR.sub.5                                                                          R.sub.4                                                                           E   G     SM  a  b  c  d  e  Note                                                                              mp                               __________________________________________________________________________    E1  4-OMe                                                                             3-F (CH.sub.2).sub.3                                                                  4-chloro-                                                                           K   15 150                                                                              12 10 500                                                                              E1                                                   phenyl                                                        E2  4-OMe                                                                             3-F (CH.sub.2).sub.3                                                                  4-bromo-                                                                            CL6 16 150                                                                              10.3                                                                             10 500                                                                              E2                                                   phenyl                                                        E3  4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  3-tri-                                                                              CL7 22.8                                                                             200                                                                              15.7                                                                             15.7                                                                             300                                                                              E2                                                   fluoro-                                                                       methyl-                                                                       phenyl                                                        E4  4-OMe                                                                             3-F (CH.sub.2).sub.2                                                                  2,4-di-                                                                             CL8 16 100                                                                              17.6                                                                             25 400                                                                              E2  88-90                                            chloro-                                                                       phenyl                                                        E5  4-OMe                                                                             3-F (CH.sub.2).sub.3                                                                  2,4-di-                                                                             CL9 13.4                                                                             150                                                                              9  10 500                                                                              E3                                                   chloro-                                                                       phenyl                                                        E6  4-OMe                                                                             3-Cl                                                                              (CH.sub.2).sub.3                                                                  phenyl                                                                              CL10                                                                              41.8                                                                             300                                                                              44.6                                                                             38 1000                                                                             E4  72.5-73.5                        E7  4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.2                                                                  4-chloro-                                                                           CL12                                                                              25 50 20.9                                                                             18 25 E5                                                   phenyl                                                        E8  4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.4                                                                  4-chloro-                                                                           CL13                                                                              23.7                                                                             100                                                                              17.6                                                                             17.5                                                                             100                                                                              E6                                                   phenyl                                                        E9  4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.4                                                                  phenyl                                                                              CL14                                                                              25.2                                                                             200                                                                              21.7                                                                             21.8                                                                             100                                                                              E6                                   E10 4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.5                                                                  4-chloro-                                                                           CL15                                                                              11 50 7.7                                                                              7.7                                                                              50 E6                                                   phenyl                                                        E11 4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  4-bromo-                                                                            CL6 15 100                                                                              10 10 250                                                                              E4  83-84                                            phenyl                                                        E12 4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  3,4-di-                                                                             CL16                                                                              30 200                                                                              20.5                                                                             20.6                                                                             100                                                                              E6                                                   chloro-                                                                       phenyl                                                        E13 4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.4                                                                  4-methoxy-                                                                          CL17                                                                              15.3                                                                             200                                                                              11.5                                                                             11.5                                                                             100                                                                              E5                                                   phenyl                                                        E14 4-OMe                                                                             3-Br                                                                              (CH.sub.2).sub.3                                                                  phenyl                                                                              CL10                                                                              25.4                                                                             100                                                                              30 23.4                                                                             400                                                                              E4  81-82                            E15 4-OMe                                                                             3-OMe                                                                             W   phenyl                                                                              CL18                                                                              20 150                                                                              16.2                                                                             14.7                                                                             450                                                                              E7  117-119                          E16 4-OMe                                                                             3-Cl                                                                              (CH.sub.2).sub.3                                                                  2-chloro-                                                                           CL2 12.4                                                                             100                                                                              10 9.7                                                                              150                                                                              E4  92-93                                            phenyl                                                        E17 4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  2-tri-                                                                              CL19                                                                              14 100                                                                              10 10 500                                                                              E8  102-104                                          fluoro-                                                                       methyl-                                                                       phenyl                                                        E18 4-OMe                                                                             3-F (CH.sub.2).sub.3                                                                  2-chloro-                                                                           CL2 19.2                                                                             150                                                                              14 11.5                                                                             500                                                                              E2                                                   phenyl                                                        E19 4-OMe                                                                             3-F (CH.sub.2).sub.3                                                                  phenyl                                                                              CL10                                                                              16.5                                                                             150                                                                              14 11.5                                                                             500                                                                              E2                                   E20 2-OMe                                                                             H   (CH.sub.2).sub.3                                                                  4-chloro-                                                                           K   12.1                                                                             100                                                                              8  9.5                                                                              50 E9  103-105                                          phenyl                                                        E21 4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.2                                                                  phenyl                                                                              CL21                                                                              16 100                                                                              16 15.9                                                                             50 E6                                   E22 4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.5                                                                  phenyl                                                                              CL22                                                                              20 100                                                                              15.7                                                                             18.2                                                                             200                                                                              E2                                   E23 4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  2-naphthyl                                                                          CL24                                                                              6  100                                                                              4  3.5                                                                              60  E10                                                                              95-96                            E24 4-OMe                                                                             3-Cl                                                                              W   phenyl                                                                              CL18                                                                              13 100                                                                              10.8                                                                             10.6                                                                             500                                                                               E11                                                                              129-131                          E25 3-OMe                                                                             4-Cl                                                                              (CH.sub.2).sub.3                                                                  phenyl                                                                              CL10                                                                              14.2                                                                             50 13.6                                                                             25 150                                                                               E12                                 E26 4-OMe                                                                             2-Cl                                                                              (CH.sub.2).sub.3                                                                  phenyl                                                                              CL10                                                                              7.5                                                                              100                                                                              8.3                                                                              7  100                                                                              E2                                           3-OMe                             E12                                 E27 5-OMe                                                                             2-Cl                                                                              (CH.sub.2).sub.3                                                                  phenyl                                                                              CL10                                                                              14.2                                                                             150                                                                              14 11.5                                                                             500                                                                              E1                                   E28 4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  2,4-di-                                                                             CL9 9  75 7.3                                                                              9  75  E13                                                 chloro-                                                                       phenyl                                                        E29 4-OMe                                                                             H   (CH.sub.2).sub.3                                                                  2-chloro-                                                                           CL2 23 80 15.1                                                                             15 100                                                                               E13                                                 phenyl                                                        E30 4-OMe                                                                             3-Ph                                                                              (CH.sub.2).sub.3                                                                  2-chloro-                                                                           CL2 9.1                                                                              50 10 9  170                                                                               E14                                                                              110-113                                          phenyl                                                        E31 4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  3-chloro-                                                                           CL25                                                                              6  50 5.7                                                                              6  50  E13                                                 phenyl                                                        E32 4-OBz                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  phenyl                                                                              CL10                                                                              15.2                                                                             250                                                                              20 26 500                                                                              E2                                   E33 4-OBz                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  2-methoxy-                                                                          CL26                                                                              11.4                                                                             100                                                                              13.2                                                                             9.2                                                                              200                                                                               E15                                                 phenyl                                                        E34 4-OBz                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  3-methoxy-                                                                          CL27                                                                              8.75                                                                             150                                                                              10.4                                                                             9  175                                                                               E16                                                 phenyl                                                        E35 4-OBz                                                                             3-OMe                                                                             (CH.sub.2).sub.2                                                                  2-chloro-                                                                           CL11                                                                              8.64                                                                             50 11.8                                                                             30 100                                                                              E2                                                   phenyl                                                        E36 4-OBz                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  2-chloro-                                                                           CL2 15 100                                                                              22 83 300                                                                              E2                                                   phenyl                                                        E37 4-OBz                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  2,4-di-                                                                             CL9 15 100                                                                              16.8                                                                             11.8                                                                             500                                                                              E2                                                   chloro-                                                                       phenyl                                                        E38 4-OBz                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  2-methyl-                                                                           CL31                                                                              7.2                                                                              20 7.7                                                                              8  100                                                                               E17                                                 thio-                                                                         phenyl                                                        E39 4-OMe                                                                             3-OMe                                                                             (CH.sub.2).sub.3                                                                  4-bi- CL29                                                                              8.9                                                                              100                                                                              9.1                                                                              9  400                                                                               E18                                                 phenylyl                                                      E40 4-OBz                                                                             3-OMe                                                                             (CH.sub.2).sub.5                                                                  phenyl                                                                              CL22                                                                              14.5                                                                             100                                                                              18.4                                                                             12.9                                                                             400                                                                              E2                                   E41 4-OBz                                                                             3-OMe                                                                             (CH.sub.2).sub.4                                                                  2-chloro                                                                            CL23                                                                              6.9                                                                              100                                                                              10.8                                                                             13 400                                                                               E19                                                 phenyl                                                        E42 4-OMe                                                                             3-F (CH.sub.2).sub.3                                                                  2-bromo-                                                                            CL1 14 100                                                                              9  10 500                                                                              E3  112-114                                          phenyl                                                        E43 4-OBz                                                                             3-OMe                                                                             W   2-chloro-                                                                           CL30                                                                              12.9                                                                             400                                                                              8.7                                                                              20 100                                                                              E2                                                   phenyl                                                        __________________________________________________________________________

EXAMPLE E44

A solution of 1-phenylcyclobutanecarbonyl chloride (129 g) indichloromethane (500 ml) was added under nitrogen over 1.5 hours to astirred mixture of 4-methoxyphenethylamine (99.5 g), dichloromethane(500 ml) and triethylamine (110 ml). The mixture was stirred at 20°-25°C. for one hour and allowed to stand for 16 hours. The reaction mixturewas washed with 2N hydrochloric acid, water and 2N aqueous sodiumhydroxide solution, dried and evaporated to giveN-[2-(4-methoxyphenyl)ethy]-1-phenylcyclobutane carboxamide.

EXAMPLE E45

A solution of 1-(1-naphthyl)cyclopropane carbonyl chloride (7.1 g,prepared as described in Example CL32) in ethyl acetate (50 ml) wasadded to a stirred mixture of 4-benzyloxy-3-methoxyphenethylaminehydrochloride (9.29 g) in ethyl acetate (150 ml). Triethylamine (25 ml)was added and the mixture stirred for a further 64 hours. The organiclayer was washed with dilute hydrochloric acid, dried over sodiumsulphate and the solvent removed in vacuo to yieldN-[2-(4-benzyloxy-3-methoxyphenyl)-ethyl]-1-(1-naphthyl)cyclopropanecarboxamide (14.1 g).

EXAMPLE E46

Cyclobutanecarbonyl chloride (19 g) was added dropwise at ambienttemperature to a stirred solution of 3,4-dimethoxyphenethylamine (30.5g) and triethylamine (23.5 ml) in tetrahydrofuran (11). After 1.5 hoursthe mixture was poured onto dilute hydrochloric acid (1 l) and theproduct was extracted into ethyl acetate. The extracts yieldedN-[2-(3,4-dimethoxyphenyl)ethyl]cyclobutanecarboxamide (44 g) which wasused without further purification.

EXAMPLES CL ##STR36##

1-Arylcycloalkanecarbonyl chlorides of formula XV were prepared byheating 1-arylcycloalkane carboxylic acids of formula XVIII (a gprepared as described in the Example identified in column SM of TableCL) and thionyl chloride (b g) under reflux for c hours. The requiredproduct was obtained by distillation under reduced pressure. The boilingpoint is given in the last column of Table CL. Where the1-arylcyclobutane carboxylic acid is a known compound or is commerciallyavailable, this is shown by a K in column SM.

In Table CL W represents --CH₂.CMe₂.CH₂ --.

                                      TABLE CL                                    __________________________________________________________________________    Ex  E   G         SM a  b  c  bp                                              __________________________________________________________________________    CL1 (CH.sub.2).sub.3                                                                  2-bromophenyl                                                                           H1 12 8.4                                                                              2  140°/3 mbar                              CL2 (CH.sub.2).sub.3                                                                  2-chlorophenyl                                                                          H2 13 11 2.5                                                                              170-172°/20 mbar                         CL3 (CH.sub.2).sub.3                                                                  4-fluorophenyl                                                                          H3 25 23 2  141-146°/20 mbar                         CL4 (CH.sub.2).sub.3                                                                  2-methylphenyl                                                                          H4 15 14 2  180°/30 mbar                             CL5 (CH.sub.2).sub.3                                                                  2-fluorophenyl                                                                          H5 25 41 2-3                                                                              115-120°/10 mbar                         CL6 (CH.sub.2).sub.3                                                                  4-bromophenyl                                                                           H6 34 49 4  120-122°/3 mbar                          CL7 (CH.sub.2).sub.3                                                                  3-trifluoromethyl-                                                                      H19                                                                              25 123                                                                              2  95-99°/0.6 mbar                                  phenyl                                                                CL8 (CH.sub.2).sub.2                                                                  2,4-dichlorophenyl                                                                      K  20 30 2  128-130°/1 mbar                          CL9 (CH.sub.2).sub.3                                                                  2,4-dichlorophenyl                                                                      H7 55 58 3  126-132°/1.5 mbar                        CL10                                                                              (CH.sub.2).sub.3                                                                  phenyl    K  75 245                                                                              2  64°/0.1 mbar-                                                          80°/0.1 mbar                             CL11                                                                              (CH.sub.2).sub.2                                                                  2-chlorophenyl                                                                          K  146.5                                                                            177.3                                                                            3  93°/0.5 mbar                             CL12                                                                              (CH.sub.2).sub.2                                                                  4-chlorophenyl                                                                          K  50 66 1.5                                                                              106-108°/1 mbar                          CL13                                                                              (CH.sub.2).sub.4                                                                  4-chlorophenyl                                                                          K  25 30 1  122-124°/1 mbar                          CL14                                                                              (CH.sub.2).sub.4                                                                  phenyl    K  25 34 2  180-182°/30 mbar                         CL15                                                                              (CH.sub.2).sub.5                                                                  4-chlorophenyl                                                                          K  13 14 1  112°/0.5 mbar                            CL16                                                                              (CH.sub.2).sub.3                                                                  3,4-dichlorophenyl                                                                      K  58 62 2  134°/2 mbar                              CL17                                                                              (CH.sub.2).sub.4                                                                  4-methoxyphenyl                                                                         K  25 30 2  204-206°/3 mbar                          CL18                                                                              W   phenyl    H8 49 74 2  70-74°/0.4 mbar                          CL19                                                                              (CH.sub.2).sub.3                                                                  2-trifluoromethyl-                                                                      H9 36 52.5                                                                             1.5                                                                              78-82°/1 mbar                                    phenyl                                                                CL20                                                                              (CH.sub.2).sub.3                                                                  4-trifluoromethoxy-                                                                     H10                                                                              6.6                                                                              3.9                                                                              3  120-                                                    phenyl                125°/0.26 mbar                           CL21                                                                              (CH.sub.2).sub.2                                                                  phenyl    K  20 20 2  154-156°/30 mbar                         CL22                                                                              (CH.sub.2).sub.5                                                                  phenyl    K  47 65.5                                                                             2  98-102°/1.5 mbar                         CL23                                                                              (CH.sub.2).sub.4                                                                  2-chlorophenyl                                                                          H17                                                                              6.8                                                                              11.5                                                                             2  120-122°/2 mbar                          CL24                                                                              (CH.sub.2).sub.3                                                                  2-naphthyl                                                                              H11                                                                              12 9.5                                                                              2.5                                                                              230°/30 mbar                             CL25                                                                              (CH.sub.2).sub.3                                                                  3-chlorophenyl                                                                          H12                                                                              88 110                                                                              2.5                                                                              120-124°/3 mbar                          CL26                                                                              (CH.sub.2).sub.3                                                                  2-methoxyphenyl                                                                         H13                                                                              20 49 2  98-102°/0.6 mbar                         CL27                                                                              (CH.sub.2).sub.3                                                                  3-methoxyphenyl                                                                         H14                                                                              56.7                                                                             120                                                                              2  126-132°/2 mbar                          CL28                                                                              (CH.sub.2).sub.3                                                                  4-methoxyphenyl                                                                         H18                                                                              21 164                                                                              2  130°/˜1/mbar                       CL29                                                                              (CH.sub.2).sub.3                                                                  4-biphenylyl                                                                            K  17 49 4  ND                                              CL30                                                                              W   2-chlorophenyl                                                                          H16                                                                              9.1                                                                              16.4                                                                             2  64-68°/0.1 mbar                          __________________________________________________________________________

EXAMPLE CL31

1-(2-Methylthiophenyl)cyclobutane carboxylic acid (12.1 g, prepared asdescribed in Example H15) was heated under reflux for 1 hour withthionyl chloride (12 ml). Excess thionyl chloride was removed bydistillation and the residue was used without further purification.

EXAMPLE CL32

1-(1-Naphthyl)cyclopropane carboxylic acid (6.7 g, prepared in a similarmanner to that described in Example H20), was added to thionyl chloride(25 ml) and the mixture heated at 90°-95° C. for 1 hour. Excess thionylchloride was removed in vacuo to yield1-(1-naphthyl)cyclopropanecarbonyl chloride (7.1 g) which was usedwithout further purification.

EXAMPLES H ##STR37##

A mixture of a 1-arylcycloalkane carbonitrile of formula XIV (a gprepared as described in the Example identified in column SM of TableH), a solution of potassium hydroxide (b g) in either water (c ml) orethylene glycol (d ml) was heated under reflux until the reaction wascomplete. Acidification of the reaction mixture gave the required1-arylcycycloalkane carboxylic acid of formula XVIII, the melting pointof which is given in the last column of Table H.

Notes to Table H

Where the starting carbonitrile is known, this is indicated by K incolumn SM.

W represents --CH₂.CMe₂.CH₂ --

ND indicates that the melting point was not determined.

H1 The product was recrystallised from a mixture of ethyl acetate andpetroleum ether (b.p. 60°-80° C.).

H2 The cooled reaction solution was washed with ethyl acetate andfiltered. The filtrate was acidified and extracted with ethyl acetate.The extract yielded a solid which was recrystallised from petroleumether (b.p. 60°-80° C.).

H3 The acidified reaction mixture was extracted with ether, the extractswashed with water and brine, then dried over magnesium sulphate andconcentrated. The residue was recrystallised from petroleum ether (b.p.60°-80° C.).

H4 The reaction mixture was poured onto water, acidified and extractedwith ethyl acetate to yield the desired product.

H5 The reaction mixture was poured onto water, acidified and extractedwith ethyl acetate to yield a gum which solidified on standing. Thissolid was dissolved in 5N aqueous sodium hydroxide solution, stirred for30 minutes then washed with ethyl acetate. The aqueous phase wasreacidified and the resulting solid collected by filtration and dried inair.

                                      TABLE H                                     __________________________________________________________________________    Ex E   G         SM a  b  c  d  Note                                                                             mp                                         __________________________________________________________________________    H1 (CH.sub.2).sub.3                                                                  2-bromophenyl                                                                           K  20 40 500      122-124                                    H2 (CH.sub.2).sub.3                                                                  2-chlorophenyl                                                                          N1 15 10.7  44    112-114                                    H3 (CH.sub.2).sub.3                                                                  4-fluorophenyl                                                                          K  40 32    130                                                                              H1 102-104                                    H4 (CH.sub.2).sub.3                                                                  2-methylphenyl                                                                          N2 38 30    125   78-80                                      H5 (CH.sub.2).sub.3                                                                  2-fluorophenyl                                                                          K  30 80 500   H2 88-89                                      H6 (CH.sub.2).sub.3                                                                  4-bromophenyl                                                                           K  34 16    150   108-110                                    H7 (CH.sub.2).sub.3                                                                  2,4-dichlorophenyl                                                                      N3 52 26    200   149-154                                    H8 W   phenyl    N8 53 33    300   93-95                                      H9 (CH.sub.2).sub.3                                                                  2-trifluoromethyl-                                                                      N4 37 18    150   125-127                                           phenyl                                                                 H10                                                                              (CH.sub.2).sub.3                                                                  4-trifluoromethoxy-                                                                     N10                                                                              5  2.9   12 H3 55-58                                             phenyl                                                                 H11                                                                              (CH.sub.2).sub.3                                                                  2-naphthyl                                                                              K  14 9.2   37    127-129                                    H12                                                                              (CH.sub.2).sub.3                                                                  3-chlorophenyl                                                                          K  85 50    243   100-104                                    H13                                                                              (CH.sub.2).sub.3                                                                  2-methoxyphenyl                                                                         N5 25 15    150   ND                                         H14                                                                              (CH.sub.2).sub.3                                                                  3-methoxyphenyl                                                                         N6 55 33    250   ND                                         H15                                                                              (CH.sub.2).sub.3                                                                  2-methylthiophenyl                                                                      N7 13.6                                                                             9     10 H4 ND                                         H16                                                                              W   2-chlorophenyl                                                                          N11                                                                              8.6                                                                              5     50    ND                                         H17                                                                              (CH.sub.2).sub.4                                                                  2-chlorophenyl                                                                          N12                                                                              16.7                                                                             10.6  50 H5 ND                                         __________________________________________________________________________

EXAMPLE H18

A mixture of 1-(4-methoxyphenyl)cyclobutane carbonitrile (41 g),potassium hydroxide (20 g) and diethylene glycol (160 ml) was heatedunder reflux for 3.5 hours. The mixture was added to water, acidifiedwith dilute hydrochloric acid and extracted with ether. The extractyielded 1-(4-methoxyphenyl)cyclobutane carboxylic acid.

EXAMPLE H19

A solution of sodium hydroxide (2.8 g) in water (4 ml) was added to astirred solution of 1-(3-trifluoromethylphenyl)cyclobutanecarbonitrile(50 g) in industrial methylated spirits (350 ml). To this was addedhydrogen peroxide (100 vol. 105 ml) dropwise over 1 hour at atemperature of ˜40° C. The mixture was then heated at 50° C. for 1 hour,allowed to cool, acidified with 5% sulphuric acid (˜40 ml) andconcentrated in vacuo. The residue was partitioned between water andether. The organic extracts were washed with water, dried (MgSO₄),filtered and evaporated in vacuo to yield a colourless oil (63 g) whichwas dissolved in dioxan (350 ml). Concentrated hydrochloric acid (75 ml)was added and the solution cooled to 5° C. A solution of sodium nitrite(27 g) in water (60 ml) was added dropwise whilst maintaining thetemperature at ˜10° C. The mixture was then heated at 90°-95° C.overnight. The mixture was cooled and the organic layer isolated. Theaqueous layer was extracted with ether and the combined organic layersdried, filtered and concentrated in vacuo to yield1-(3-trifluoromethylphenyl)cyclobutane carboxylic acid.

EXAMPLE H20

A mixture of 1-(1-naphthyl)cyclopropanecarbonitrile (60.7 g, prepared ina similar manner to that described in Example N9) and 10% aqueouspotassium hydroxide solution was stirred and heated under reflux for 16hours. Ethylene glycol (250 ml) was added and the mixture was heatedunder reflux for 5 hours. Each time complete solution was achieved,further water was added to cloud point. Water (500 ml) was added and themixture was allowed to stand for 16 hours. The resulting solid wasremoved by filtration. The filtrate was diluted with water (800 ml),filtered, and the filtrate acidified by addition of dilute hydrochloricacid. The resulting solid was collected by filtration, washed with waterand dried in air, yielding 1-(1-naphthyl)cyclopropane carboxylic acid(25.9 g).

EXAMPLES N ##STR38##

A mixture of an arylacetonitrile of formula XX (a g) and1,3-dibromopropane (b g) and either ether (c ml) or dimethylsulphoxide(d ml) was added dropwise to a stirred suspension of powdered potassiumhydroxide (e g) in dimethylsulphoxide (f ml). The reaction mixture wasthen treated by method A, B, C, D or E.

Method A

The mixture was heated at 30°-35° C. for 3 hours (2 hours for ExampleN3) and then poured into a mixture of ice/water and concentratedhydrochloric acid at below 15° C. and filtered. The filtrate wasextracted with ether. The extract gave an oil which was distilled togive the desired 1-arylcyclobutanecarbonitrile of formula XIV, theboiling point of which is given in Table N.

Method B

The mixture was stirred at ambient temperature for 16 hours and pouredinto water. The mixture was extracted with ethyl acetate. The extractyielded an oil which was distilled to give the desired1-arylcyclobutanecarbonitrile of formula XIV, the boiling point of whichis given in Table N.

Method C

The mixture was stirred at ambient temperature for 16 hours and pouredinto water. The resulting precipitate was collected by filtration anddissolved in ether. The filtrate was extracted with ether. The solutionand extracts were combined and yielded an oil which was distilled togive the desired 1-arylcyclobutanecarbonitrile of formula XIV, theboiling point of which is given in Table N.

Method D

The mixture was stirred at ambient temperature for 3 hours, then at30°-35° C. for 3 hours, then poured into a mixture of ice/water andconcentrated hydrochloric acid. The mixture was washed with ether andthe organic extracts washed with water, dried, filtered and the solventevaporated to give the desired 1-arylcyclobutanecarbonitrile of formulaXIV, the boiling point of which is given in Table N.

Method E

The starting nitrile was prepared as described in Example R. The mixturewas stirred at ambient temperature for 1 hour and poured into water. Themixture was extracted with ethyl acetate. The extract yielded an oilwhich was distilled. The fraction with a boiling point greater than 160°C. was purified by flash chromatography using a 1:9 mixture of petroleumether and ethyl acetate as eluant. The solvent was evaporated to givethe desired 1-arylcyclobutanecarbonitrile of formula XIV.

                                      TABLE N                                     __________________________________________________________________________    Ex                                                                              G        a  b  c  d  e  f   Method                                                                             bp                                         __________________________________________________________________________    N1                                                                              2-chlorophenyl                                                                         50 71 150   79 300 A    108-112°/1 mbar                     N2                                                                              2-methylphenyl                                                                         50 77    115                                                                              87 500 B    165-175°/20 mbar                    N3                                                                              2,4-dichloro-                                                                          100                                                                              120                                                                              250   132                                                                              500 A    128-134°/0.7 mbar                     phenyl                                                                      N4                                                                              2-trifluoro-                                                                           50 71    100                                                                              61 500 B    92-98°/1 mbar                         methylphenyl                                                                N5                                                                              2-methoxyphenyl                                                                        150                                                                              222   200                                                                              269                                                                              1400                                                                              C    142-148°/1.0 mbar                   N6                                                                              3-methoxyphenyl                                                                        100                                                                              165                                                                              200   181.5                                                                            375 D    114-118°/3.4 mbar                   N7                                                                              2-methylthio-                                                                          26.2                                                                             35.7  100                                                                              42.4                                                                             200 E    ND                                           phenyl                                                                      __________________________________________________________________________

EXAMPLE N8

A mixture of phenylacetonitrile (47.4 g) and1,3-diiodo-2,2-dimethylpropane (131.2 g) was added dropwise over 2 hoursat 25° C. to a stirred solution of powdered potassium hydroxide (90.7 g)in dry dimethylsulphoxide (600 ml) under a nitrogen atmosphere. Themixture was stirred overnight then poured onto water and extracted withether (1000 ml). The extracts were decolourised with charcoal, filteredand concentrated in vacuo to yield an orange-brown oil which wasdistilled under vacuum to give 2,2-dimethyl-1-phenylcyclobutanecarbonitrile, (b.p. 101°-106° C./0.6mbar) as a pale yellow oil.

EXAMPLE N9

A solution of 1-naphthylacetonitrile (53 g) in 1-bromo-2-chloroethane(35.2 ml) was added over 35 minutes to a vigorously stirred mixture ofbenzyltriethylammonium chloride (2 g) and 50% w/v aqueous sodiumhydroxide solution (190 ml) at approximately 70° C. The mixture washeated at 75°-80° C. for 2 hours, then 1-bromo-2-chloro-ethane (15 ml)and benzyltriethylammonium chloride (1 g) were added and heatingcontinued for 4.5 hours. After standing for 16 hours,1-bromo-2-chloroethane (10 ml), benzyltriethylammonium chloride (1 g)and solid sodium hydroxide (20 g) were added. The mixture was stirredand heated at 75°-80° C. for 6 hours. The aqueous layer was washed withether and the combined organic layers yielded an oil which was distilled(b.p. 135° C./0.07 mbar) to give a distillate which solidified oncooling. The solid, 1-(1-naphthyl)cyclopropanecarbonitrile was usedwithout further purification.

EXAMPLE N10

A solution of 4-trifluoromethoxyphenylacetonitrile (38.9 g) and1,3-dibromopropane (39.1 g) in tetrahydrofuran (50 ml) was added underargon to a stirred solution of 50% sodium hydride (19.2 g) intetrahydrofuran (200 ml) and dimethylformamide (25 ml) at 25°-30° C.over 1 hour. The mixture was stirred at 20° C. for 1.5 hours, then at30°-40° C. for 1 hour, then cooled and water added. The mixture wasfiltered and washed with ether. The organic layer was washed with water,dried over magnesium sulphate and the solvent removed by evaporation.The residue was distilled (b.p. 111°-117° C./10 mbar) to give1-(4-trifluoromethoxyphenyl)cyclobutanecarbonitrile (30.98 g).

EXAMPLE N11

A mixture of 2-chlorophenylacetonitrile (26.5 g),1,3-diiodo-2,2-dimethylpropane (56 g) and dimethyl sulphoxide (300 ml)was added dropwise to a stirred suspension of powdered potassiumhydroxide (40 g) in dry dimethylsulphoxide (300 ml). The mixture wasstirred for one hour, then poured onto ice/water and extracted withethyl acetate. The extracts yielded an oil which was distilled undervacuum to give 2,2-dimethyl-1-(2-chlorophenyl)cyclobutane carbonitrile,(b.p. 116°-120° C./1 mbar) which was recrystallised from petroleum ether(b.p. 60°-80° C.) m.p. 65°-69° C.

EXAMPLE N12

A mixture of 2-chlorophenylacetonitrile (20 g), 1,4-dibromobutane (28.5g) and dimethyl sulphoxide (100 ml) was added dropwise to a stirredsuspension of powdered potassium hydroxide (26 g) in drydimethylsulphoxide (300 ml). The mixture was stirred for one hour, thenpoured onto ice/water and extracted with ethyl acetate. The extractsyielded an oil which was distilled under vacuum (b.p. 112°-116° C./1mbar) to give 1-(2-chlorophenyl)cyclopentanecarbonitrile (16.7 g).

EXAMPLE P

Methyl iodide (110 g was added dropwise to a stirred solution of4-chloro-3-methylphenol (100 g) and potassium carbonate (194 g) inacetone (500 ml). The mixture was stirred for 1.5 hours. Methyl iodide(142 g) was added and the mixture stirred for a further hour. Solventwas removed by evaporation and the residue partitioned between water andethyl acetate. The organic layer yielded an oil which was heated underreflux for 2 hours with N-bromosuccinimide (119 g) and benzoyl peroxide(1 g) in carbon tetrachloride (250 ml). The mixture was cooled, filteredand the filtrate concentrated to give a residue which was distilledunder high vacuum. The fractions collected between 88° and 94° C./0.4mbar were recrystallised from petroleum ether (b.p. 60°-80° C.) to give2-chloro-5-methoxy benzyl bromide, m.p. 51°-52° C.

Sodium cyanide (10.4 g) was added portionwise to a stirred solution ofthe above benzyl bromide (25 g) in a 2:1 mixture of ethanol and water(250 ml). The mixture was stirred for one hour at 50° C., poured intowater and extracted with ether. The extract gave2-chloro-5-methoxy-phenylacetonitrile (m.p. 62°-65° C.). 10MBoranemethylsulphide complex (11.3 ml) was added dropwise under nitrogento a refluxing solution of the above phenylacetonitrile (18.6 g) intetrahydrofuran (150 ml). The mixture was heated under reflux for 2hours and dilute hydrochloric acid was added dropwise and the acidifiedmixture heated at 95° C. for one hour. The cooled mixture was washedwith ether, basified with dilute sodium hydroxide solution and extractedwith ether. The extract yielded 2 -chloro-5-methoxyphenethylamine as ayellow oil.

EXAMPLE Q

A mixture of tetrakis triphenylphosphine palladium (7 g),3-bromo-4-methoxyphenethylamine hydrobromide (62.2 g) and toluene (400ml) was stirred under nitrogen with 2M aqueous sodium carbonate solution(200 ml) and then a solution of phenyl boric acid (26.8 g) in ethanol(100 ml) was added. The mixture was heated under reflux for 48 hoursthen cooled and treated with 30% aqueous hydrogen peroxide solution (10ml). The mixture was stirred at ambient temperature for 1 hour. Theaqueous layer was separated and extracted with ether. The ether extractswere combined with the original organic phase. Distillation yielded4-methoxy-3-phenylphenethylamine which was used without furtherpurification.

EXAMPLE R

Phosphorus tribromide (75 g) in toluene (50 ml) was added to a stirredmixture of 2-methylthiobenzyl alcohol (42.5 g) in toluene (25 ml) over10 minutes at 5° C. The mixture was then stirred at 40° C. for 1 hour,water (100 ml) was added and stirring continued at ambient temperaturefor 1 hour. The organic layer was separated and the aqueous layerextracted with ethyl acetate. The combined organic layers yielded anoil. The oil (58.6 g) was dissolved in a 1:2 mixture of water andethanol and sodium cyanide (26.5 g) was added over 15 minutes. Themixture was stirred at 50° C. for 1.5 hours then poured onto water (500ml) and extracted with ethyl acetate. The extract yielded2-methylthiophenylacetonitrile.

EXAMPLE 94

The use of compounds of the present invention in the manufacture ofpharmaceutical compositions is illustrated by the following description.In this description the term "active compound" denotes any compound ofthe invention but particularly any compound which is the final productof one of the preceding Examples.

a) Capsules

In the preparation of capsules, 10 parts by weight of active compoundand 240 parts by weight of lactose are de-aggregated and blended. Themixture is filled into hard gelatin capsules, each capsule containing aunit dose of part of a unit dose of active compound.

b) Tablets

Tablets are prepared from the following ingredients.

    ______________________________________                                                       Parts by weight                                                ______________________________________                                        Active compound  10                                                           Lactose          190                                                          Maize starch     22                                                           Polyvinylpyrrolidone                                                                           10                                                           Magnesium stearate                                                                             3                                                            ______________________________________                                    

The active compound, the lactose and some of the starch arede-aggregated, blended and the resulting mixture is granulated with asolution of the polyvinylpyrrolidone in ethanol. The dry granulate isblended with the magnesium stearate and the rest of the starch. Themixture is then compressed in a tabletting machine to give tablets eachcontaining a unit dose or a part of a unit dose of active compound.

c) Enteric coated tablets

Tablets are prepared by the method described in (b) above. The tabletsare enteric coated in a conventional manner using a solution of 20%cellulose acetate phthalate and 3% diethyl phthalate inethanol:dichloromethane (1:1).

d) Suppositories

In the preparation of suppositories, 100 parts by weight of activecompound is incorporated in 1300 parts by weight of triglyceridesuppository base and the mixture formed into suppositories eachcontaining a therapeutically effective amount of active ingredient.

We claim:
 1. A tetrahydroisoquinoline compound of formula I ##STR39## or a pharmaceutically acceptable salt thereof, in which, R₁ represents one or more substituents selected from H, halo, hydroxy, alkyl of 1 to 3 carbon atoms (optionally substituted by hydroxy), alkoxy of 1 to 3 carbon atoms, alkylthio of 1 to 3 carbon atoms, alkylsulphinyl of 1 to 3 carbon atoms, alkylsulphonyl of 1 to 3 carbon atoms, nitro, cyano, polyhaloalkyl of 1 to 3 carbon atoms, polyhaloalkoxy of 1 to 3 carbon atoms, phenyl (optionally substituted by one or more substituents selected from halo, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms), or R₁ is carbamoyl optionally alkylated by one or two alkyl groups each independently of 1 to 3 carbon atoms;R₂ represents an aliphatic group containing 1 to 3 carbon atoms optionally substituted by hydroxy or alkoxy containing 1 to 3 carbon atoms; E represents an alkylene chain containing 2 to 5 carbon atoms optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms, and G represents phenyl or phenyl substituted by one or more substituents which may be the same or different, and which are independently alkyl of 1 to 3 carbon polyhaloalkyl of 1 to 3 carbon atoms, halo, hydroxy, polyhaloalkyl of 1 to 3 carbon atoms, polyhaloalkoxy of atoms, alkylsulphinyl of 1 to 3 carbon atoms, alkylsulphonyl of 1 to 3 carbon atoms, phenyl (optionally substituted by one or more substituents selected from halo, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms), carbamoyl optionally alkylated by one or two alkyl groups each independently of 1 to 3 carbon atoms, or G represents a phenyl ring having fused thereto a heterocyclic or aromatic carbocyctic ring; and compounds of formula I which are O-acylated in the 5, 6, 7, or 8-position in the tetrahydroisoquinoline ring.
 2. A tetrahydroisoquinoline compound of formula I as claimed in claim 1 wherein R₁ represents H, halo, hydroxy, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, alkylthio of 1 to 3 carbon atoms, nitro, polyfluoroalkyl of 1 to 3 carbon atoms, polyfluoroalkoxy of 1 to 3 carbon atoms or phenyl optionally substituted by fluoro, chloro, bromo, methyl or methoxy.
 3. A tetrahydroisoquinoline compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein R₁ represents H, fluoro, chloro, bromo, hydroxy, methyl, methoxy, phenyl or nitro.
 4. A tetrahydroisoquinoline compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein R₂ represents an alkyl group containing 1 to 3 carbon atoms optionally substituted by hydroxy or by methoxy or R₂ represents an alkenyl group of 2 or 3 carbon atoms.
 5. A tetrahydroisoquinoline compound of formula I as claimed in claim 4 or a pharmaceutically acceptable salt thereof, wherein R₂ represents methyl, ethyl, 2-hydroxyethyl or 2-methoxyethyl or R₂ represents allyl.
 6. A tetrahydroisoquinoline compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein the group E represents --(CH₂)₂ --, --(CH₂)₃ --, --(CH₂)₄ --, --(CH₂)₅ -- or --CH₂ CMe₂ CH₂ --.
 7. A tetrahydroisoquinoline compound of formula I as claimed in claim 1 pharmaceutically acceptable salt thereof, wherein G represents phenyl or phenyl substituted by one or more substituents which are independently alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halo, hydroxy, polyfluoroalkyl of 1 to 3 carbon atoms, polyfluoroalkoxy of 1 to 3 carbon atoms or phenyl optionally substituted by fluoro, chloro, bromo, methyl or methoxy or G represents naphthyl or dihydrobenzofuran-7-yl.
 8. A tetrahydroisoquinoline compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein G represents phenyl or phenyl substituted by methyl, hydroxy, methoxy, methylthio, fluoro, chloro, bromo, trifluoromethyl, cyano or trifluoromethoxy or G represents a naphthyl or dihydrobenzo[b]furan-7-yl group.
 9. A tetrahydroisoquinoline compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein G represents phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-fluorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methylthiophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethoxyphenyl, 2-cyanophenyl, 2-bromo-4,5- dimethoxyphenyl, 1-naphthyl, 2-naphthyl or 2,3-dihydrobenzo[b]furan-7-yl.
 10. A tetrahydroisoquinoline compound of formula II ##STR40## or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, E and G are as defined in any preceding claim and compounds of formula II which are O-acylated in the 7 position in the tetrahydroisoquinoline ring.
 11. A tetrahydroisoquinoline compound of formula I represented by compounds of formula III ##STR41## or a pharmaceutically acceptable salt thereof, in which R₁, R₂, E and G are as defined in claim 1 and R₇ represents an acyl group derived from a carboxylic acid having 6 to 20 carbon atoms.
 12. A tetrahydroisoquinoline compound of formula III as claimed in claim 11 or a pharmaceutically acceptable salt thereof, wherein R₇ represents heptanoyl, decanoyl, dodecanoyl, hexadecanoyl or octadecanoyl.
 13. A tetrahydroisoquinoline compound of formula III as claimed in claim 11 or a pharmaceutically acceptable salt thereof, wherein the group OR₇ is in the 7-position.
 14. A tetrahydroisoquinoline compound of formula I as claimed in claim 1 selected from the group consisting of:1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline 1-[1-(2- chlorophenyl)cyclopropyl]-7-hydroxy-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline 1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-2,6-dimethyl-1,2,3,4-tetrahydroisoquinoline 1-[1-(2-chlorophenyl)cyclopropyl]-8-decanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline 1-[1-(2-chlorophenyl)cyclopropyl]-7-dodecanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline 1-[1-(2 -chlorophenyl)cyclopropyl]-7-hexadecanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline 1-[1-(2-chlorophenyl)cyclopropyl]-7-octadecanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline 1-[1-(2-chlorophenyl)cyclopropyl]-7-decanoyloxy-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline 1-[1-(2-chlorophenyl)cyclobutyl]-7-decanoyloxy-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolineor a pharmaceutically acceptable salt thereof in the form of individual enantiomers, racemates or other mixtures of enantiomers.
 15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, together with a pharmaceutically acceptable diluent or carrier.
 16. A method of providing analgesia or of treating psychoses, Parkinson's disease, Lesch-Nyan syndrome, attention deficit disorder or cognitive impairment or in the relief of drug dependence or tardive dyskinesia which comprises the administration of a therapeutically effective amount of a compound of formula I as claimed in claim 1 to a patient in need thereof.
 17. A method as claimed in claim 16 for treating schizophrenia.
 18. The method of claim 16 for treating psychoses. 